These are representative sample records from Science.gov related to your search topic.
For comprehensive and current results, perform a real-time search at Science.gov.
1

Expression of Histone Deacetylases HDAC1, HDAC2, HDAC3, and HDAC6 in Invasive Ductal Carcinomas of the Breast  

PubMed Central

Purpose DNA deacetylation by histone deacetylase (HDAC) is an important mechanism involved in the oncogenic tumorigenesis of breast cancer. Previous studies have reported an association of the estrogen receptor (ER) with HDACs and demonstrated the efficacy of HDAC inhibitors for the treatment of breast cancers via in vitro experiments. In this study, we examined the association of HDAC expression with clinicopathological parameters and disease-specific survival. Methods Immunohistochemical (IHC) analysis of HDAC1, HDAC2, HDAC3, and HDAC6 was performed using tissue microarrays in 300 invasive ductal carcinomas. IHC scoring was determined by multiplication of the intensity (0 to 3) and the proportion (0 to 4) of staining, and we classified tumors into low- and high-HDAC expression groups. Results High expression of HDAC1 was correlated with the molecular subtype (p=0.001) and human epidermal growth factor 2 (HER2) amplification (p=0.012). High expression of HDAC6 was correlated with a younger age (p<0.001), ER expression (p=0.025), progesterone receptor expression (p=0.034), molecular subtype (p=0.023), and HER2 amplification (p=0.011). High HDAC1 expression was correlated with luminal A tumors (p=0.001), while high HDAC6 expression was more common in luminal B tumors (p=0.023). Although the expression of HDACs did not exhibit prognostic significance in the entire cohort, high expression of HDAC1 and HDAC6 was associated with improved overall survival (OS) in patients with ER-positive tumors (p=0.017 and p=0.029, respectively), and high expression of HDAC2 was correlated with improved OS in ER-negative tumors (p=0.048) on univariate analysis. Furthermore, high HDAC6 expression was associated with improved disease-free survival (p=0.048) on multivariate analysis. Conclusion HDAC1 expression is significantly correlated with the molecular subtypes of tumors, with the highest expression being observed in luminal A tumors. HDAC6 is a significantly correlated with ER expression and the molecular subtype, thereby supporting the estrogen regulatory property of HDAC6. HDAC1 and HDAC6 expression are good prognostic factors for ER-positive tumors. PMID:25548579

Seo, Jinwon; Park, Hye-Rim; Kim, Dong Hoon; Kwon, Mi Jung; Kim, Lee Su; Ju, Young-Su

2014-01-01

2

Structural Snapshots of Human HDAC8 Provide Insights into the Class I Histone Deacetylases  

Microsoft Academic Search

Modulation of the acetylation state of histones plays a pivotal role in the regulation of gene expression. Histone deacetylases (HDACs) catalyze the removal of acetyl groups from lysines near the N termini of histones. This reaction promotes the condensation of chromatin, leading to repression of transcription. HDAC deregulation has been linked to several types of cancer, suggesting a potential use

John R. Somoza; Robert J. Skene; Bradley A. Katz; Clifford Mol; Joseph D. Ho; Andy J. Jennings; Christine Luong; Andrew Arvai; Joseph J Buggy; Ellen Chi; Jie Tang; Bi-Ching Sang; Erik Verner; Robert Wynands; Ellen M Leahy; Douglas R Dougan; Gyorgy Snell; Marc Navre; Mark W Knuth; Ronald V Swanson; Duncan E McRee; Leslie W Tari

2004-01-01

3

Hydroxamic acid-based histone deacetylase (HDAC) inhibitors can mediate neuroprotection independent of HDAC inhibition.  

PubMed

Histone deacetylase (HDAC) inhibition improves function and extends survival in rodent models of a host of neurological conditions, including stroke, and neurodegenerative diseases. Our understanding, however, of the contribution of individual HDAC isoforms to neuronal death is limited. In this study, we used selective chemical probes to assess the individual roles of the Class I HDAC isoforms in protecting Mus musculus primary cortical neurons from oxidative death. We demonstrated that the selective HDAC8 inhibitor PCI-34051 is a potent neuroprotective agent; and by taking advantage of both pharmacological and genetic tools, we established that HDAC8 is not critically involved in PCI-34051's mechanism of action. We used BRD3811, an inactive ortholog of PCI-34051, and showed that, despite its inability to inhibit HDAC8, it exhibits robust neuroprotective properties. Furthermore, molecular deletion of HDAC8 proved insufficient to protect neurons from oxidative death, whereas both PCI-34051 and BRD3811 were able to protect neurons derived from HDAC8 knock-out mice. Finally, we designed and synthesized two new, orthogonal negative control compounds, BRD9715 and BRD8461, which lack the hydroxamic acid motif and showed that they stably penetrate cell membranes but are not neuroprotective. These results indicate that the protective effects of these hydroxamic acid-containing small molecules are likely unrelated to direct epigenetic regulation via HDAC inhibition, but rather due to their ability to bind metals. Our results suggest that hydroxamic acid-based HDAC inhibitors may mediate neuroprotection via HDAC-independent mechanisms and affirm the need for careful structure-activity relationship studies when using pharmacological approaches. PMID:25339746

Sleiman, Sama F; Olson, David E; Bourassa, Megan W; Karuppagounder, Saravanan S; Zhang, Yan-Ling; Gale, Jennifer; Wagner, Florence F; Basso, Manuela; Coppola, Giovanni; Pinto, John T; Holson, Edward B; Ratan, Rajiv R

2014-10-22

4

Histone deacetylase 3 (hdac3) is specifically required for liver development in zebrafish.  

PubMed

Histone deacetylases (HDACs) are key transcription regulators that function by deacetylating histones/transcription factors and modifying chromatin structure. In this work, we showed that chemical inhibition of HDACs by valproic acid (VPA) led to impaired liver development in zebrafish mainly by inhibiting specification, budding, and differentiation. Formation of exocrine pancreas but not endocrine pancreas was also inhibited. The liver defects induced by VPA correlate with suppressed total HDAC enzymatic activity, but are independent of angiogenesis inhibition. Gene knockdown by morpholino demonstrated that hdac3 is specifically required for liver formation while hdac1 is more globally required for multiple development processes in zebrafish including liver/exocrine pancreas formation. Furthermore, overexpression of hdac3 but not hdac1 partially rescued VPA induced small liver. One mechanism by which hdac3 regulates zebrafish liver growth is through inhibiting growth differentiation factor 11 (gdf11), a unique target of hdac3 and a member of the transforming growth factor beta family. Simultaneous overexpression or morpholino knockdown showed that hdac3 and gdf11 function antagonistically in zebrafish liver development. These results revealed a novel and specific role of hdac3 in liver development and the distinct functions between hdac1 and hdac3 in zebrafish embryonic development. PMID:18367159

Farooq, Muhammad; Sulochana, K N; Pan, Xiufang; To, Jiawei; Sheng, Donglai; Gong, Zhiyuan; Ge, Ruowen

2008-05-01

5

Histone deacetylase 3 (HDAC3) as a novel therapeutic target in multiple myeloma  

PubMed Central

Histone deacetylases (HDACs) represent novel molecular targets for the treatment of various types of cancers, including multiple myeloma (MM). Many HDAC inhibitors have already shown remarkable anti-tumor activities in the preclinical setting; however, their clinical utility is limited due to unfavorable toxicities associated with their broad range HDAC inhibitory effects. Isoform-selective HDAC inhibition may allow for MM cytotoxicity without attendant side effects. In this study, we demonstrated that HDAC3 knockdown and a small molecule HDAC3 inhibitor BG45 trigger significant MM cell growth inhibition via apoptosis, evidenced by caspase and PARP cleavage. Importantly, HDAC3 inhibition downregulates phosphorylation (tyrosine 705 and serine 727) of STAT3. Neither IL-6 nor bone marrow stromal cells overcome this inhibitory effect of HDAC3 inhibition on p-STAT3 and MM cell growth. Moreover, HDAC3 inhibition also triggers hyperacetylation of STAT3, suggesting crosstalk signaling between phosphorylation and acetylation of STAT3. Importantly, inhibition of HDAC3, but not HDAC1 or HDAC2, significantly enhances bortezomib-induced cytotoxicity. Finally, we confirm that BG45 alone and in combination with bortezomib trigger significant tumor growth inhibition in vivo in a murine xenograft model of human MM. Our results indicate that HDAC3 represents a promising therapeutic target, and validate a prototype novel HDAC3 inhibitor BG45 in MM. PMID:23913134

Minami, Jiro; Suzuki, Rikio; Mazitschek, Ralph; Gorgun, Gullu; Ghosh, Balaram; Cirstea, Diana; Hu, Yiguo; Mimura, Naoya; Ohguchi, Hiroto; Cottini, Francesca; Jakubikova, Jana; Munshi, Nikhil C.; Haggarty, Stephen J.; Richardson, Paul G.; Hideshima, Teru; Anderson, Kenneth C.

2014-01-01

6

The large subunit of replication factor C interacts with the histone deacetylase, HDAC1.  

PubMed

Replication factor C (RFC) is a pentameric complex of five distinct subunits that functions as a clamp loader, facilitating the loading of proliferating cell nuclear antigen (PCNA) onto DNA during replication and repair. More recently the large subunit of RFC, RFC (p140), has been found to interact with the retinoblastoma (Rb) tumor suppressor and the CCAAT/enhancer-binding protein alpha (C/EBP alpha) transcription factor. We now report that RFC (p140) associates with histone deacetylase activity and interacts with histone deacetylase 1 (HDAC1). This complex is functional and when targeted to promoters as a Gal4 fusion, RFC (p140) is a strong, deacetylase-dependent repressor of transcription. Further analysis revealed that RFC (p140) contains two distinct transcriptional repression domains. Moreover, both of these domains interact separately with HDAC1. PMID:12045192

Anderson, Lisa A; Perkins, Neil D

2002-08-16

7

Histone Deacetylase 7 (Hdac7) Suppresses Chondrocyte Proliferation and ?-Catenin Activity during Endochondral Ossification.  

PubMed

Histone deacetylases (Hdacs) regulate endochondral ossification by suppressing gene transcription and modulating cellular responses to growth factors and cytokines. We previously showed that Hdac7 suppresses Runx2 activity and osteoblast differentiation. In this study, we examined the role of Hdac7 in postnatal chondrocytes. Hdac7 was highly expressed in proliferating cells within the growth plate. Postnatal tissue-specific ablation of Hdac7 with a tamoxifen-inducible collagen type 2a1-driven Cre recombinase increased proliferation and ?-catenin levels in growth plate chondrocytes and expanded the proliferative zone. Similar results were obtained in primary chondrocyte cultures where Hdac7 was deleted with adenoviral-Cre. Hdac7 bound ?-catenin in proliferating chondrocytes, but stimulation of chondrocyte maturation promoted the translocation of Hdac7 to the cytoplasm where it was degraded by the proteasome. As a result, ?-catenin levels and transcription activity increased in the nucleus. These data demonstrate that Hdac7 suppresses proliferation and ?-catenin activity in chondrocytes. Reducing Hdac7 levels in early chondrocytes may promote the expansion and regeneration of cartilage tissues. PMID:25389289

Bradley, Elizabeth W; Carpio, Lomeli R; Olson, Eric N; Westendorf, Jennifer J

2015-01-01

8

In vivo imaging of histone deacetylases (HDACs) in the central nervous system and major peripheral organs.  

PubMed

Epigenetic enzymes are now targeted to treat the underlying gene expression dysregulation that contribute to disease pathogenesis. Histone deacetylases (HDACs) have shown broad potential in treatments against cancer and emerging data supports their targeting in the context of cardiovascular disease and central nervous system dysfunction. Development of a molecular agent for non-invasive imaging to elucidate the distribution and functional roles of HDACs in humans will accelerate medical research and drug discovery in this domain. Herein, we describe the synthesis and validation of an HDAC imaging agent, [(11)C]6. Our imaging results demonstrate that this probe has high specificity, good selectivity, and appropriate kinetics and distribution for imaging HDACs in the brain, heart, kidney, pancreas, and spleen. Our findings support the translational potential for [(11)C]6 for human epigenetic imaging. PMID:25203558

Wang, Changning; Schroeder, Frederick A; Wey, Hsiao-Ying; Borra, Ronald; Wagner, Florence F; Reis, Surya; Kim, Sung Won; Holson, Edward B; Haggarty, Stephen J; Hooker, Jacob M

2014-10-01

9

Histone Deacetylase HDAC4 Promotes Gastric Cancer SGC-7901 Cells Progression via p21 Repression  

PubMed Central

Gastric cancer (GC) is one of the leading causes of cancer death in the world. The role of histone deacetylase 4 (HDAC4) in specific cell and tissue types has been identified. However, its biological roles in the development of gastric cancer remain largely unexplored. Quantitative real time PCR (qRT-PCR) and western blot were used to analyze the expression of HDAC4 in the clinical samples. siRNA and overexpression of HDAC4 and siRNA p21 were used to study functional effects in a proliferation, a colony formation, a adenosine 5?-triphosphate (ATP) assay and reactive oxygen species(ROS) generation, cell cycle, cell apoptosis rates, and autophagy assays. HDAC4 was up-regulated in gastric cancer tissues and several gastric cancer cell lines. The proliferation, colony formation ability and ATP level were enhanced in HDAC4 overexpression SGC-7901 cells, but inhibited in HDAC4 knockdown SGC-7901 cells. HDAC4 knockdown led to G0/G1 phase cell arrest and caused apoptosis and ROS increase. Moreover, HDAC4 was found to inhibit p21 expression in gastric cancer SGC-7901 cells. p21 knockdown dramatically attenuated cell proliferation inhibition, cell cycle arrest, cell apoptosis promotion and autophagy up-regulation in HDAC4-siRNA SGC-7901 cells. We demonstrated that HDAC4 promotes gastric cancer cell progression mediated through the repression of p21. Our results provide an experimental basis for understanding the pro-tumor mechanism of HDAC4 as treatment for gastric cancer. PMID:24896240

Zhang, Wen-Liang; Zhang, Jian-Tao; Yuan, Chun-Hua; Zhao, Ping-Wei; Lin, Yu-Yang; Hong, Sen; Li, Chen-Yao; Wang, Lei

2014-01-01

10

The role of class I histone deacetylase (HDAC) on gluconeogenesis in liver  

SciTech Connect

Research highlights: {yields} A novel class I HDAC inhibitor decreased hepatic PEPCK mRNA and gluconeogenesis. {yields} Inhibition of HDAC decreased PEPCK by reducing HNF4{alpha} expression and FoxO1 activity. {yields} siRNA knockdown of HDAC1 in HepG2 cells reduced the expression of PEPCK and HNF4{alpha}. {yields} Inhibition of class I HDAC improves glucose homeostasis in HFD mice. -- Abstract: Hepatic gluconeogenesis is crucial for glucose homeostasis. Although sirtuin 1 (Sirt1) is implicated in the regulation of gluconeogenesis in the liver, the effects of other histone deacetylases (HDAC) on gluconeogenesis are unclear. The aim of this study was to identify the role of class I HDACs in hepatic gluconeogenesis. In HepG2 cells and the liver of mice, the expressions of phosphoenol pyruvate carboxykinase (PEPCK) and hepatocyte nuclear factor 4{alpha} (HNF4{alpha}) were significantly decreased by treatment with a newly designed class I HDAC inhibitor, Ky-2. SiRNA knockdown of HDAC1 expression, but not of HDAC2 or HDAC3, in HepG2 cells decreased PEPCK and HNF4{alpha} expression. In HepG2 cells, insulin-stimulated phosphorylation of Akt and forkhead box O 1 (FoxO1) was increased by Ky-2. Pyruvate tolerance tests in Ky-2-treated high-fat-diet (HFD)-fed mice showed a marked reduction in blood glucose compared with vehicle-treated HFD mice. These data suggest that class I HDACs increase HNF4{alpha} protein expression and the transcriptional activity of FoxO1, followed by the induction of PEPCK mRNA expression and gluconeogenesis in liver.

Oiso, Hiroshi [Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto (Japan)] [Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto (Japan); Furukawa, Noboru, E-mail: n-furu@gpo.kumamoto-u.ac.jp [Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto (Japan)] [Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto (Japan); Suefuji, Mihoshi; Shimoda, Seiya [Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto (Japan)] [Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto (Japan); Ito, Akihiro; Furumai, Ryohei [Chemical Genetics Laboratory, RIKEN Advanced Science Institute, Saitama (Japan)] [Chemical Genetics Laboratory, RIKEN Advanced Science Institute, Saitama (Japan); Nakagawa, Junichi [Department of Food Science and Technology, Faculty of Bio-Industry, Tokyo University of Agriculture, Hokkaido (Japan)] [Department of Food Science and Technology, Faculty of Bio-Industry, Tokyo University of Agriculture, Hokkaido (Japan); Yoshida, Minoru [Chemical Genetics Laboratory, RIKEN Advanced Science Institute, Saitama (Japan)] [Chemical Genetics Laboratory, RIKEN Advanced Science Institute, Saitama (Japan); Nishino, Norikazu [Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, Kitakyushu (Japan)] [Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, Kitakyushu (Japan); Araki, Eiichi [Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto (Japan)] [Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto (Japan)

2011-01-07

11

Nuclear receptor co-repressors are required for the histone-deacetylase activity of HDAC3 in vivo.  

PubMed

Histone deacetylase 3 (HDAC3) is an epigenome-modifying enzyme that is required for normal mouse development and tissue-specific functions. In vitro, HDAC3 protein itself has minimal enzyme activity but gains its histone-deacetylation function from stable association with the conserved deacetylase-activating domain (DAD) contained in nuclear receptor co-repressors NCOR1 and SMRT. Here we show that HDAC3 enzyme activity is undetectable in mice bearing point mutations in the DAD of both NCOR1 and SMRT (NS-DADm), despite having normal levels of HDAC3 protein. Local histone acetylation is increased, and genomic HDAC3 recruitment is reduced though not abrogated. Notably, NS-DADm mice are born and live to adulthood, whereas genetic deletion of HDAC3 is embryonic lethal. These findings demonstrate that nuclear receptor co-repressors are required for HDAC3 enzyme activity in vivo and suggest that a deacetylase-independent function of HDAC3 may be required for life. PMID:23292142

You, Seo-Hee; Lim, Hee-Woong; Sun, Zheng; Broache, Molly; Won, Kyoung-Jae; Lazar, Mitchell A

2013-02-01

12

Differential effects of binge methamphetamine injections on the mRNA expression of histone deacetylases (HDACs) in the rat striatum.  

PubMed

Methamphetamine use disorder is characterized by recurrent binge episodes. Humans addicted to methamphetamine experience various degrees of cognitive deficits and show evidence of neurodegenerative processes in the brain. Binge injections of METH to rodents also cause significant toxic changes in the brain. In addition, this pattern of METH injections can alter gene expression in the dorsal striatum. Gene expression is regulated, in part, by histone deacetylation. We thus tested the possibility that METH toxic doses might cause changes in the mRNA levels of histone deacetylases (HDACs). We found that METH did produce significant decreases in the mRNA expression of HDAC8, which is a class I HDAC. METH also decreased expression of HDAC6, HDAC9, and HDAC10 that are class II HDACs. The expression of the class IV HDAC, HDAC11, was also suppressed by METH. The expression of Sirt2, Sirt5, and Sirt6 that are members of class III HDACs was also downregulated by METH injections. Our findings implicate changes in HDAC expression may be an early indicator of impending METH-induced neurotoxicity in the striatum. This idea is consistent with the accumulated evidence that some HDACs are involved in neurodegenerative processes in the brain. PMID:25452209

Omonijo, Oluwaseyi; Wongprayoon, Pawaris; Ladenheim, Bruce; McCoy, Michael T; Govitrapong, Piyarat; Jayanthi, Subramaniam; Cadet, Jean Lud

2014-12-01

13

Statins Increase p21 through Inhibition of Histone Deacetylase Activity and Release of Promoter-Associated HDAC1\\/2  

Microsoft Academic Search

Statins are 3-hydroxy-3-methylglutaryl-CoA reductase inhi- bitors broadly used for the control of hypercholesterolemia. Recently, they are reported to have beneficial effects on cer- tain cancers. In this study, we show that statins inhibited the histone deacetylase (HDAC) activity and increased the accumulation of acetylated histone-H3 and the expression of p21WAF\\/CIP in human cancer cells. Computational modeling showed the direct interaction

Yi-Chu Lin; Jung-Hsin Lin; Chia-Wei Chou; Yu-Fan Chang; Shu-Hao Yeh; Ching-Chow Chen

2008-01-01

14

Snail Mediates E-Cadherin Repression by the Recruitment of the Sin3A/Histone Deacetylase 1 (HDAC1)/HDAC2 Complex  

PubMed Central

The transcription factor Snail has been described as a direct repressor of E-cadherin expression during development and carcinogenesis; however, the specific mechanisms involved in this process remain largely unknown. Here we show that mammalian Snail requires histone deacetylase (HDAC) activity to repress E-cadherin promoter and that treatment with trichostatin A (TSA) is sufficient to block the repressor effect of Snail. Moreover, overexpression of Snail is correlated with deacetylation of histones H3 and H4 at the E-cadherin promoter, and TSA treatment in Snail-expressing cells reverses the acetylation status of histones. Additionally, we demonstrate that Snail interacts in vivo with the E-cadherin promoter and recruits HDAC activity. Most importantly, we demonstrate an interaction between Snail, histone deacetylase 1 (HDAC1) and HDAC2, and the corepressor mSin3A. This interaction is dependent on the SNAG domain of Snail, indicating that the Snail transcription factor mediates the repression by recruitment of chromatin-modifying activities, forming a multimolecular complex to repress E-cadherin expression. Our results establish a direct causal relationship between Snail-dependent repression of E-cadherin and the modification of chromatin at its promoter. PMID:14673164

Peinado, Hector; Ballestar, Esteban; Esteller, Manel; Cano, Amparo

2004-01-01

15

Histone deacetylase (HDAC) inhibitor kinetic rate constants correlate with cellular histone acetylation but not transcription and cell viability.  

PubMed

Histone deacetylases (HDACs) are critical in the control of gene expression, and dysregulation of their activity has been implicated in a broad range of diseases, including cancer, cardiovascular, and neurological diseases. HDAC inhibitors (HDACi) employing different zinc chelating functionalities such as hydroxamic acids and benzamides have shown promising results in cancer therapy. Although it has also been suggested that HDACi with increased isozyme selectivity and potency may broaden their clinical utility and minimize side effects, the translation of this idea to the clinic remains to be investigated. Moreover, a detailed understanding of how HDACi with different pharmacological properties affect biological functions in vitro and in vivo is still missing. Here, we show that a panel of benzamide-containing HDACi are slow tight-binding inhibitors with long residence times unlike the hydroxamate-containing HDACi vorinostat and trichostatin-A. Characterization of changes in H2BK5 and H4K14 acetylation following HDACi treatment in the neuroblastoma cell line SH-SY5Y revealed that the timing and magnitude of histone acetylation mirrored both the association and dissociation kinetic rates of the inhibitors. In contrast, cell viability and microarray gene expression analysis indicated that cell death induction and changes in transcriptional regulation do not correlate with the dissociation kinetic rates of the HDACi. Therefore, our study suggests that determining how the selective and kinetic inhibition properties of HDACi affect cell function will help to evaluate their therapeutic utility. PMID:23897821

Lauffer, Benjamin E L; Mintzer, Robert; Fong, Rina; Mukund, Susmith; Tam, Christine; Zilberleyb, Inna; Flicke, Birgit; Ritscher, Allegra; Fedorowicz, Grazyna; Vallero, Roxanne; Ortwine, Daniel F; Gunzner, Janet; Modrusan, Zora; Neumann, Lars; Koth, Christopher M; Lupardus, Patrick J; Kaminker, Joshua S; Heise, Christopher E; Steiner, Pascal

2013-09-13

16

Histone deacetylase (HDAC) 1 and 2 are essential for accurate cell division and the pluripotency of embryonic stem cells.  

PubMed

Histone deacetylases 1 and 2 (HDAC1/2) form the core catalytic components of corepressor complexes that modulate gene expression. In most cell types, deletion of both Hdac1 and Hdac2 is required to generate a discernible phenotype, suggesting their activity is largely redundant. We have therefore generated an ES cell line in which Hdac1 and Hdac2 can be inactivated simultaneously. Loss of HDAC1/2 resulted in a 60% reduction in total HDAC activity and a loss of cell viability. Cell death is dependent upon cell cycle progression, because differentiated, nonproliferating cells retain their viability. Furthermore, we observe increased mitotic defects, chromatin bridges, and micronuclei, suggesting HDAC1/2 are necessary for accurate chromosome segregation. Consistent with a critical role in the regulation of gene expression, microarray analysis of Hdac1/2-deleted cells reveals 1,708 differentially expressed genes. Significantly for the maintenance of stem cell self-renewal, we detected a reduction in the expression of the pluripotent transcription factors, Oct4, Nanog, Esrrb, and Rex1. HDAC1/2 activity is regulated through binding of an inositol tetraphosphate molecule (IP4) sandwiched between the HDAC and its cognate corepressor. This raises the important question of whether IP4 regulates the activity of the complex in cells. By rescuing the viability of double-knockout cells, we demonstrate for the first time (to our knowledge) that mutations that abolish IP4 binding reduce the activity of HDAC1/2 in vivo. Our data indicate that HDAC1/2 have essential and pleiotropic roles in cellular proliferation and regulate stem cell self-renewal by maintaining expression of key pluripotent transcription factors. PMID:24958871

Jamaladdin, Shereen; Kelly, Richard D W; O'Regan, Laura; Dovey, Oliver M; Hodson, Grace E; Millard, Christopher J; Portolano, Nicola; Fry, Andrew M; Schwabe, John W R; Cowley, Shaun M

2014-07-01

17

Histone deacetylase (HDAC) 1 and 2 are essential for accurate cell division and the pluripotency of embryonic stem cells  

PubMed Central

Histone deacetylases 1 and 2 (HDAC1/2) form the core catalytic components of corepressor complexes that modulate gene expression. In most cell types, deletion of both Hdac1 and Hdac2 is required to generate a discernible phenotype, suggesting their activity is largely redundant. We have therefore generated an ES cell line in which Hdac1 and Hdac2 can be inactivated simultaneously. Loss of HDAC1/2 resulted in a 60% reduction in total HDAC activity and a loss of cell viability. Cell death is dependent upon cell cycle progression, because differentiated, nonproliferating cells retain their viability. Furthermore, we observe increased mitotic defects, chromatin bridges, and micronuclei, suggesting HDAC1/2 are necessary for accurate chromosome segregation. Consistent with a critical role in the regulation of gene expression, microarray analysis of Hdac1/2-deleted cells reveals 1,708 differentially expressed genes. Significantly for the maintenance of stem cell self-renewal, we detected a reduction in the expression of the pluripotent transcription factors, Oct4, Nanog, Esrrb, and Rex1. HDAC1/2 activity is regulated through binding of an inositol tetraphosphate molecule (IP4) sandwiched between the HDAC and its cognate corepressor. This raises the important question of whether IP4 regulates the activity of the complex in cells. By rescuing the viability of double-knockout cells, we demonstrate for the first time (to our knowledge) that mutations that abolish IP4 binding reduce the activity of HDAC1/2 in vivo. Our data indicate that HDAC1/2 have essential and pleiotropic roles in cellular proliferation and regulate stem cell self-renewal by maintaining expression of key pluripotent transcription factors. PMID:24958871

Jamaladdin, Shereen; Kelly, Richard D. W.; O’Regan, Laura; Dovey, Oliver M.; Hodson, Grace E.; Millard, Christopher J.; Portolano, Nicola; Fry, Andrew M.; Schwabe, John W. R.; Cowley, Shaun M.

2014-01-01

18

Activation of the growth-differentiation factor 11 gene by the histone deacetylase (HDAC) inhibitor trichostatin A and repression by HDAC3.  

PubMed

Histone deacetylase (HDAC) inhibitors inhibit the proliferation of transformed cells in vitro, restrain tumor growth in animals, and are currently being actively exploited as potential anticancer agents. To identify gene targets of the HDAC inhibitor trichostatin A (TSA), we compared the gene expression profiles of BALB/c-3T3 cells treated with or without TSA. Our results show that TSA up-regulates the expression of the gene encoding growth-differentiation factor 11 (Gdf11), a transforming growth factor beta family member that inhibits cell proliferation. Detailed analyses indicated that TSA activates the gdf11 promoter through a conserved CCAAT box element. A comprehensive survey of human HDACs revealed that HDAC3 is necessary and sufficient for the repression of gdf11 promoter activity. Chromatin immunoprecipitation assays showed that treatment of cells with TSA or silencing of HDAC3 expression by small interfering RNA causes the hyperacetylation of Lys-9 in histone H3 on the gdf11 promoter. Together, our results provide a new model in which HDAC inhibitors reverse abnormal cell growth by inactivation of HDAC3, which in turn leads to the derepression of gdf11 expression. PMID:15169878

Zhang, Xiaohong; Wharton, Walker; Yuan, Zhigang; Tsai, Shih-Chang; Olashaw, Nancy; Seto, Edward

2004-06-01

19

Dietary histone deacetylase inhibitors  

PubMed Central

Sulforaphane (SFN) is an isothiocyanate found in cruciferous vegetables, such as broccoli and broccoli sprouts. This anticarcinogen was first identified as a potent inducer of Phase 2 detoxification enzymes, but evidence is mounting that SFN also acts through epigenetic mechanisms. SFN has been shown to inhibit histone deacetylase (HDAC) activity in human colon and prostate cancer lines, with an increase in global and local histone acetylation status, such as on the promoter regions of P21 and bax genes. SFN also inhibited the growth of prostate cancer xenografts and spontaneous intestinal polyps in mouse models, with evidence for altered histone acetylation and HDAC activities in vivo. In human subjects, a single ingestion of 68 g broccoli sprouts inhibited HDAC activity in circulating peripheral blood mononuclear cells 3-6 h after consumption, with concomitant induction of histone H3 and H4 acetylation. These findings provide evidence that one mechanism of cancer chemoprevention by SFN is via epigenetic changes associated with inhibition of HDAC activity. Other dietary agents such as butyrate, biotin, lipoic acid, garlic organosulfur compounds, and metabolites of vitamin E have structural features compatible with HDAC inhibition. The ability of dietary compounds to de-repress epigenetically silenced genes in cancer cells, and to activate these genes in normal cells, has important implications for cancer prevention and therapy. In a broader context, there is growing interest in dietary HDAC inhibitors and their impact on epigenetic mechanisms affecting other chronic conditions, such as cardiovascular disease, neurodegeneration and aging. PMID:17555985

Dashwood, Roderick H.; Ho, Emily

2009-01-01

20

The class II histone deacetylase HDAC4 regulates cognitive, metabolic and endocrine functions through its expression in osteoblasts  

PubMed Central

Objective The recently described endocrine functions of osteoblasts raise questions about their transcriptional regulation. Thus far, this aspect of osteoblast biology has been addressed only by examining the role of transcription factors binding to specific cis-acting elements in the promoter of the Osteocalcin gene. Methods In contrast, the role of chromatin remodeling enzymes, such as histone deacetylases (HDACs), in this process has not as yet been thoroughly understood. Results Here we show that through its expression in osteoblasts, one class II HDAC molecule, HDAC4, favors Osteocalcin expression, and as a result, the physiological functions regulated by osteocalcin such as spatial learning, memory, male fertility and insulin secretion. Molecular and genetic evidence indicates that through its expression in osteoblasts HDAC4 fulfills these long-range functions in part by stabilizing the transcription factor ATF4. Remarkably, through its expression in osteoblasts, HDAC4 also enhances appetite, a physiological function that is not regulated by osteocalcin. Conclusions These results provide a more in depth molecular understanding of the regulation of the endocrine functions of the osteoblast, and suggest the existence of additional hormones synthesized by osteoblasts that also regulate appetite.

Makinistoglu, Munevver Parla; Karsenty, Gerard

2014-01-01

21

Molecular basis for the antiparasitic activity of a mercaptoacetamide derivative that inhibits histone deacetylase 8 (HDAC8) from the human pathogen schistosoma mansoni.  

PubMed

Schistosomiasis, caused by the parasitic flatworm Schistosoma mansoni and related species, is a tropical disease that affects over 200 million people worldwide. A new approach for targeting eukaryotic parasites is to tackle their dynamic epigenetic machinery that is necessary for the extensive phenotypic changes during the life cycle of the parasite. Recently, we identified S. mansoni histone deacetylase 8 (smHDAC8) as a potential target for antiparasitic therapy. Here, we present results on the investigations of a focused set of HDAC (histone deacetylase) inhibitors on smHDAC8. Besides several active hydroxamates, we identified a thiol-based inhibitor that inhibited smHDAC8 activity in the micromolar range with unexpected selectivity over the human isotype, which has not been observed so far. The crystal structure of smHDAC8 complexed with the thiol derivative revealed that the inhibitor is accommodated in the catalytic pocket, where it interacts with both the catalytic zinc ion and the essential catalytic tyrosine (Y341) residue via its mercaptoacetamide warhead. To our knowledge, this is the first complex crystal structure of any HDAC inhibited by a mercaptoacetamide inhibitor, and therefore, this finding offers a rationale for further improvement. Finally, an ester prodrug of the thiol HDAC inhibitor exhibited antiparasitic activity on cultured schistosomes in a dose-dependent manner. PMID:24657767

Stolfa, Diana A; Marek, Martin; Lancelot, Julien; Hauser, Alexander-Thomas; Walter, Alexandra; Leproult, Emeline; Melesina, Jelena; Rumpf, Tobias; Wurtz, Jean-Marie; Cavarelli, Jean; Sippl, Wolfgang; Pierce, Raymond J; Romier, Christophe; Jung, Manfred

2014-10-01

22

HDAC8 Substrates: Histones and Beyond  

PubMed Central

The lysine deacetylase family of enzymes (HDACs) was first demonstrated to catalyze deacetylation of acetyllysine residues on histones. In subsequent years, HDACs have been shown to recognize a large pool of acetylated non-histone proteins as substrates. Recently, thousands of acetylated proteins have been discovered, yet in most cases, the HDAC that catalyzes deacetylation in vivo has not been identified. This gap has created the need for better in vivo, in vitro, and in silico approaches for determining HDAC substrates. While HDAC8 is the best kinetically and structurally characterized HDAC, few efficient substrates have yet been substantiated in vivo. In this review we delineate factors that may be important for determining HDAC8 substrate recognition and catalytic activity, including structure, complex formation, and post-translational modifications. This summary provides insight into the challenges of identifying in vivo substrates for HDAC8, and provides a good vantage point for understanding the variables important for predicting HDAC substrate recognition. PMID:23175386

Wolfson, Noah A.; Pitcairn, Carol Ann; Fierke, Carol A.

2012-01-01

23

Structural Basis for the Inhibition of Histone Deacetylase 8 (HDAC8), a Key Epigenetic Player in the Blood Fluke Schistosoma mansoni  

PubMed Central

The treatment of schistosomiasis, a disease caused by blood flukes parasites of the Schistosoma genus, depends on the intensive use of a single drug, praziquantel, which increases the likelihood of the development of drug-resistant parasite strains and renders the search for new drugs a strategic priority. Currently, inhibitors of human epigenetic enzymes are actively investigated as novel anti-cancer drugs and have the potential to be used as new anti-parasitic agents. Here, we report that Schistosoma mansoni histone deacetylase 8 (smHDAC8), the most expressed class I HDAC isotype in this organism, is a functional acetyl-L-lysine deacetylase that plays an important role in parasite infectivity. The crystal structure of smHDAC8 shows that this enzyme adopts a canonical ?/? HDAC fold, with specific solvent exposed loops corresponding to insertions in the schistosome HDAC8 sequence. Importantly, structures of smHDAC8 in complex with generic HDAC inhibitors revealed specific structural changes in the smHDAC8 active site that cannot be accommodated by human HDACs. Using a structure-based approach, we identified several small-molecule inhibitors that build on these specificities. These molecules exhibit an inhibitory effect on smHDAC8 but show reduced affinity for human HDACs. Crucially, we show that a newly identified smHDAC8 inhibitor has the capacity to induce apoptosis and mortality in schistosomes. Taken together, our biological and structural findings define the framework for the rational design of small-molecule inhibitors specifically interfering with schistosome epigenetic mechanisms, and further support an anti-parasitic epigenome targeting strategy to treat neglected diseases caused by eukaryotic pathogens. PMID:24086136

Marek, Martin; Kannan, Srinivasaraghavan; Hauser, Alexander-Thomas; Moraes Mourão, Marina; Caby, Stéphanie; Cura, Vincent; Stolfa, Diana A.; Schmidtkunz, Karin; Lancelot, Julien; Andrade, Luiza; Renaud, Jean-Paul; Oliveira, Guilherme; Sippl, Wolfgang; Jung, Manfred; Cavarelli, Jean; Pierce, Raymond J.; Romier, Christophe

2013-01-01

24

Inactivation of histone deacetylase 1 (HDAC1) but not HDAC2 is required for the glucocorticoid-dependent CCAAT/enhancer-binding protein ? (C/EBP?) expression and preadipocyte differentiation.  

PubMed

Several drugs currently used in the management of mood disorders, epilepsy (ie, valproic acid), or the control of inflammation (ie, corticosteroids) have been shown to promote visceral obesity in humans by increasing the number of newly formed adipocytes. Valproic acid is classified as a nonspecific histone deacetylase (HDAC) inhibitor, along with trichostatin A and butyric acid. In vitro experiments have demonstrated that such molecules greatly enhance the rate of preadipocyte differentiation, similarly to the effect of corticosteroids. The glucocorticoid receptor stimulates adipogenesis in part by enhancing the transcription of C/ebpa through the titration, and subsequent degradation, of HDAC1 from the C/ebp? promoter. There is, however, controversy in the literature as to the role of HDACs during adipogenesis. In this study, we sought to demonstrate, using 2 different strategies, the definite role of HDAC1 in adipogenesis. By using small interference RNA-mediated knockdown of HDAC1 and by generating an enzymatically inactive HDAC1D181A by site-directed mutagenesis, we were able to show that HDAC1, but not HDAC2, suppresses glucocorticoid receptor-potentiated preadipocyte differentiation by decreasing CCAAT/enhancer-binding protein (C/ebp)? and Ppar? expression levels at the onset of differentiation. Finally, we demonstrate that HDAC1D181A acts as a dominant negative mutant of HDAC1 during adipogenesis by modulating C/EBP? transcriptional activity on the C/ebp? promoter. PMID:25203139

Kuzmochka, Claire; Abdou, Houssein-Salem; Haché, Robert J G; Atlas, Ella

2014-12-01

25

Ginsenoside Rg3 Inhibits Melanoma Cell Proliferation through Down-Regulation of Histone Deacetylase 3 (HDAC3) and Increase of p53 Acetylation  

PubMed Central

Malignant melanoma is an aggressive and deadly form of skin cancer, and despite recent advances in available therapies, is still lacking in completely effective treatments. Rg3, a monomer extracted from ginseng roots, has been attempted for the treatment of many cancers. It is reported that the expressions of histone deacetylase 3 (HDAC3) and p53 acetylation correlate with tumor cell growth. However, the antitumor effect of Rg3 on melanoma and the mechanism by which it regulates HDAC3 expression and p53 acetylation remain unknown. We found high expression of HDAC3 in human melanoma tissues to be significantly correlated to lymph node metastasis and clinical stage of disease (p<0.05). In melanoma cells, Rg3 inhibited cell proliferation and induced G0/G1 cell cycle arrest. Rg3 also decreased the expression of HDAC3 and increased the acetylation of p53 on lysine (k373/k382). Moreover, suppression of HDAC3 by either siRNA or a potent HDAC3 inhibitor (MS-275) inhibited cell proliferation, increased p53 acetylation and transcription activity. In A375 melanoma xenograft studies, we demonstrated that Rg3 and HDAC3 short hairpin RNA (shHDAC3) inhibited the growth of xenograft tumors with down-regulation of HDAC3 expression and up-regulation of p53 acetylation. In conclusion, Rg3 has antiproliferative activity against melanoma by decreasing HDAC3 and increasing acetylation of p53 both in vitro and in vivo. Thus, Rg3 serves as a potential therapeutic agent for the treatment of melanoma. PMID:25521755

Shan, Xiu; Fu, Yuan-Shan; Aziz, Faisal; Wang, Xiao-Qi; Yan, Qiu; Liu, Ji-Wei

2014-01-01

26

Deacetylase-independent function of HDAC3 in transcription and metabolism requires nuclear receptor corepressor.  

PubMed

Histone deacetylases (HDACs) are believed to regulate gene transcription by catalyzing deacetylation reactions. HDAC3 depletion in mouse liver upregulates lipogenic genes and results in severe hepatosteatosis. Here we show that pharmacologic HDAC inhibition in primary hepatocytes causes histone hyperacetylation but does not upregulate expression of HDAC3 target genes. Meanwhile, deacetylase-dead HDAC3 mutants can rescue hepatosteatosis and repress lipogenic genes expression in HDAC3-depleted mouse liver, demonstrating that histone acetylation is insufficient to activate gene transcription. Mutations abolishing interactions with the nuclear receptor corepressor (NCOR or SMRT) render HDAC3 nonfunctional in vivo. Additionally, liver-specific knockout of NCOR, but not SMRT, causes metabolic and transcriptomal alterations resembling those of mice without hepatic HDAC3, demonstrating that interaction with NCOR is essential for deacetylase-independent function of HDAC3. These findings highlight nonenzymatic roles of a major HDAC in transcriptional regulation in vivo and warrant reconsideration of the mechanism of action of HDAC inhibitors. PMID:24268577

Sun, Zheng; Feng, Dan; Fang, Bin; Mullican, Shannon E; You, Seo-Hee; Lim, Hee-Woong; Everett, Logan J; Nabel, Christopher S; Li, Yun; Selvakumaran, Vignesh; Won, Kyoung-Jae; Lazar, Mitchell A

2013-12-26

27

Histone Deacetylase Activity Modulates Alternative Splicing  

PubMed Central

There is increasing evidence to suggest that splicing decisions are largely made when the nascent RNA is still associated with chromatin. Here we demonstrate that activity of histone deacetylases (HDACs) influences splice site selection. Using splicing-sensitive microarrays, we identified ?700 genes whose splicing was altered after HDAC inhibition. We provided evidence that HDAC inhibition induced histone H4 acetylation and increased RNA Polymerase II (Pol II) processivity along an alternatively spliced element. In addition, HDAC inhibition reduced co-transcriptional association of the splicing regulator SRp40 with the target fibronectin exon. We further showed that the depletion of HDAC1 had similar effect on fibronectin alternative splicing as global HDAC inhibition. Importantly, this effect was reversed upon expression of mouse HDAC1 but not a catalytically inactive mutant. These results provide a molecular insight into a complex modulation of splicing by HDACs and chromatin modifications. PMID:21311748

Hnilicová, Jarmila; Hozeifi, Samira; Dušková, Eva; Icha, Jaroslav; Tománková, Tereza; Stan?k, David

2011-01-01

28

Histone deacetylase activity modulates alternative splicing.  

PubMed

There is increasing evidence to suggest that splicing decisions are largely made when the nascent RNA is still associated with chromatin. Here we demonstrate that activity of histone deacetylases (HDACs) influences splice site selection. Using splicing-sensitive microarrays, we identified ?700 genes whose splicing was altered after HDAC inhibition. We provided evidence that HDAC inhibition induced histone H4 acetylation and increased RNA Polymerase II (Pol II) processivity along an alternatively spliced element. In addition, HDAC inhibition reduced co-transcriptional association of the splicing regulator SRp40 with the target fibronectin exon. We further showed that the depletion of HDAC1 had similar effect on fibronectin alternative splicing as global HDAC inhibition. Importantly, this effect was reversed upon expression of mouse HDAC1 but not a catalytically inactive mutant. These results provide a molecular insight into a complex modulation of splicing by HDACs and chromatin modifications. PMID:21311748

Hnilicová, Jarmila; Hozeifi, Samira; Dušková, Eva; Icha, Jaroslav; Tománková, Tereza; Stan?k, David

2011-01-01

29

Histone Deacetylase Inhibition with Valproic Acid Downregulates Osteocalcin Gene Expression in Human Dental Pulp Stem Cells and Osteoblasts: Evidence for HDAC2 Involvement  

PubMed Central

Adult mesenchymal stem cells, such as dental pulp stem cells, are of great interest for cell-based tissue engineering strategies because they can differentiate into a variety of tissue-specific cells, above all, into osteoblasts. In recent years, epigenetic studies on stem cells have indicated that specific histone alterations and modifying enzymes play essential roles in cell differentiation. However, although several studies have reported that valproic acid (VPA)—a selective inhibitor of histone deacetylases (HDAC)—enhances osteoblast differentiation, data on osteocalcin expression—a late-stage marker of differentiation—are limited. We therefore decided to study the effect of VPA on dental pulp stem cell differentiation. A low concentration of VPA did not reduce cell viability, proliferation, or cell cycle profile. However, it was sufficient to significantly enhance matrix mineralization by increasing osteopontin and bone sialoprotein expression. In contrast, osteocalcin levels were decreased, an effect induced at the transcriptional level, and were strongly correlated with inhibition of HDAC2. In fact, HDAC2 silencing with shRNA produced a similar effect to that of VPA treatment on the expression of osteoblast-related markers. We conclude that VPA does not induce terminal differentiation of osteoblasts, but stimulates the generation of less mature cells. Moreover, specific suppression of an individual HDAC by RNA interference could enhance only a single aspect of osteoblast differentiation, and thus produce selective effects. PMID:24105979

Paino, Francesca; la Noce, Marcel; Tirino, Virginia; Naddeo, Pasqualina; Desiderio, Vincenzo; Pirozzi, Giuseppe; De Rosa, Alfredo; Laino, Luigi; Altucci, Lucia; Papaccio, Gianpaolo

2014-01-01

30

Amino acid starvation induces reactivation of silenced transgenes and latent HIV-1 provirus via down-regulation of histone deacetylase 4 (HDAC4).  

PubMed

The epigenetic silencing of exogenous transcriptional units integrated into the genome represents a critical problem both for long-term gene therapy efficacy and for the eradication of latent viral infections. We report here that limitation of essential amino acids, such as methionine and cysteine, causes selective up-regulation of exogenous transgene expression in mammalian cells. Prolonged amino acid deprivation led to significant and reversible increase in the expression levels of stably integrated transgenes transcribed by means of viral or human promoters in HeLa cells. This phenomenon was mediated by epigenetic chromatin modifications, because histone deacetylase (HDAC) inhibitors reproduced starvation-induced transgene up-regulation, and transcriptome analysis, ChIP, and pharmacological and RNAi approaches revealed that a specific class II HDAC, namely HDAC4, plays a critical role in maintaining the silencing of exogenous transgenes. This mechanism was also operational in cells chronically infected with HIV-1, the etiological agent of AIDS, in a latency state. Indeed, both amino acid starvation and pharmacological inhibition of HDAC4 promoted reactivation of HIV-1 transcription and reverse transcriptase activity production in HDAC4(+) ACH-2 T-lymphocytic cells but not in HDAC4(-) U1 promonocytic cells. Thus, amino acid deprivation leads to transcriptional derepression of silenced transgenes, including integrated plasmids and retroviruses, by a process involving inactivation or down-regulation of HDAC4. These findings suggest that selective targeting of HDAC4 might represent a unique strategy for modulating the expression of therapeutic viral vectors, as well as that of integrated HIV-1 proviruses in latent reservoirs without significant cytotoxicity. PMID:22826225

Palmisano, Ilaria; Della Chiara, Giulia; D'Ambrosio, Rosa Lucia; Huichalaf, Claudia; Brambilla, Paola; Corbetta, Silvia; Riba, Michela; Piccirillo, Rosanna; Valente, Sergio; Casari, Giorgio; Mai, Antonello; Martinelli Boneschi, Filippo; Gabellini, Davide; Poli, Guido; Schiaffino, Maria Vittoria

2012-08-21

31

Butyrate Histone Deacetylase Inhibitors  

PubMed Central

Abstract In addition to being a part of the metabolic fatty acid fuel cycle, butyrate is also capable of inducing growth arrest in a variety of normal cell types and senescence-like phenotypes in gynecological cancer cells, inhibiting DNA synthesis and cell growth in colonic tumor cell lines, suppressing hTERT mRNA expression and telomerase activity in human prostate cancer cells, and inducing stem cell differentiation and apoptosis by DNA fragmentation. It regulates gene expression by inhibiting histone deacetylases (HDACs), enhances memory recovery and formation in mice, stimulates neurogenesis in the ischemic brain, promotes osteoblast formation, selectively blocks cell replication in transformed cells (compared to healthy cells), and can prevent and treat diet-induced obesity and insulin resistance in mouse models of obesity, as well as stimulate fetal hemoglobin expression in individuals with hematologic diseases such as the thalassemias and sickle-cell disease, in addition to a multitude of other biochemical effects in vivo. However, efforts to exploit the potential of butyrate in the clinical treatment of cancer and other medical disorders are thwarted by its poor pharmacological properties (short half-life and first-pass hepatic clearance) and the multigram doses needed to achieve therapeutic concentrations in vivo. Herein, we review some of the methods used to overcome these difficulties with an emphasis on HDAC inhibition. PMID:23514803

Boosalis, Michael S.; Perrine, Susan P.; Sangerman, José

2012-01-01

32

Functional Requirement for Histone Deacetylase 1 in Caenorhabditis elegans Gonadogenesis  

Microsoft Academic Search

Histone acetylation and deacetylation have been implicated in the regulation of gene expression. Molecular studies have shown that histone deacetylases (HDACs) function as transcriptional repressors. However, very little is known about their roles during development in multicellular organisms. We previously demonstrated that inhibition of maternal and zygotic expression of histone deacetylase 1 (HDA-1) causes embryonic lethality in Caenorhabditis elegans. Here,

Pascale Dufourcq; Martin Victor; Frédérique Gay; Jonathan Hodgkin; Yang Shi

2002-01-01

33

Histone Deacetylase Inhibitors: Potential in Cancer Therapy  

PubMed Central

The role of histone deacetylases (HDAC) and the potential of these enzymes as therapeutic targets for cancer, neurodegenerative diseases and a number of other disorders is an area of rapidly expanding investigation. There are 18 HDACs in humans. These enzymes are not redundant in function. Eleven of the HDACs are zinc dependent, classified on the basis of homology to yeast HDACs: Class I includes HDACs 1, 2, 3, and 8; Class IIA includes HDACs 4, 5, 7, and 9; Class IIB, HDACs 6 and 10; and Class IV, HDAC11. Class III HDACs, sirtuins 1–7, have an absolute requirement for NAD+, are not zinc dependent and generally not inhibited by compounds that inhibit zinc dependent deacetylases. In addition to histones, HDACs have many nonhistone protein substrates which have a role in regulation of gene expression, cell proliferation, cell migration, cell death, and angiogenesis. HDAC inhibitors (HDACi) have been discovered of different chemical structure. HDACi cause accumulation of acetylated forms of proteins which can alter their structure and function. HDACi can induce different phenotypes in various transformed cells, including growth arrest, apoptosis, reactive oxygen species facilitated cell death and mitotic cell death. Normal cells are relatively resistant to HDACi induced cell death. Several HDACi are in various stages of development, including clinical trials as monotherapy and in combination with other anti-cancer drugs and radiation. The first HDACi approved by the FDA for cancer therapy is suberoylanilide hydroxamic acid (SAHA, vorinostat, Zolinza), approved for treatment of cutaneous T-cell lymphoma. PMID:19459166

Marks, P.A.; Xu, W-S

2009-01-01

34

Histone deacetylases: target enzymes for cancer therapy  

Microsoft Academic Search

Epigenic regulation of gene transcription has recently been the subject of a fast growing interest particularly in the field\\u000a of cancer. Enzymatic acetylation and deacetylation of the epsilon-amino groups of lysine residues from nucleosomal histones,\\u000a represents major molecular epigenic mechanisms controlling gene expression. Histone deacetylases (HDACs) and histone acetyl\\u000a transferases (HAT) represent the two families of enzymes in charge of

Denis Mottet; Vincent Castronovo

2008-01-01

35

On the Inhibition of Histone Deacetylase 8  

PubMed Central

Histone deacetylases are key regulators of gene expression and have recently emerged as important therapeutic targets for cancer and a growing number of non-malignant diseases. Many widely studied inhibitors of HDACs such as SAHA are thought to have low selectivity within or between the human HDAC isoform classes. Using an isoform-selective assay, we have shown that a number of the known inhibitors have in fact a low activity against HDAC8. Based on the wealth of structural information available for human HDAC8, we use a combination of docking and molecular dynamics simulations to determine the structural origin of the experimental results. A close relationship is found between the activity and the high surface malleability of HDAC8. These results provide a rationale for the recently described “linkerless” HDAC8 selective inhibitors and design criteria for HDAC8 selective inhibitors. PMID:20472442

Estiu, Guillermina; West, Nathan; Mazitschek, Ralph; Greenberg, Edward; Bradner, James E.; Wiest, Olaf

2011-01-01

36

Design, synthesis, and evaluation of hydroxamic acid-based molecular probes for in vivo imaging of histone deacetylase (HDAC) in brain.  

PubMed

Hydroxamic acid-based histone deacetylase inhibitors (HDACis) are a class of molecules with therapeutic potential currently reflected in the use of suberoylanilide hydroxamic acid (SAHA; Vorinostat) to treat cutaneous T-cell lymphomas (CTCL). HDACis may have utility beyond cancer therapy, as preclinical studies have ascribed HDAC inhibition as beneficial in areas such as heart disease, diabetes, depression, neurodegeneration, and other disorders of the central nervous system (CNS). However, little is known about the pharmacokinetics (PK) of hydroxamates, particularly with respect to CNS-penetration, distribution, and retention. To explore the rodent and non-human primate (NHP) brain permeability of hydroxamic acid-based HDAC inhibitors using positron emission tomography (PET), we modified the structures of belinostat (PXD101) and panobinostat (LBH-589) to incorporate carbon-11. We also labeled PCI 34051 through carbon isotope substitution. After characterizing the in vitro affinity and efficacy of these compounds across nine recombinant HDAC isoforms spanning Class I and Class II family members, we determined the brain uptake of each inhibitor. Each labeled compound has low uptake in brain tissue when administered intravenously to rodents and NHPs. In rodent studies, we observed that brain accumulation of the radiotracers were unaffected by the pre-administration of unlabeled inhibitors. Knowing that CNS-penetration may be desirable for both imaging applications and therapy, we explored whether a liquid chromatography, tandem mass spectrometry (LC-MS-MS) method to predict brain penetrance would be an appropriate method to pre-screen compounds (hydroxamic acid-based HDACi) prior to PET radiolabeling. LC-MS-MS data were indeed useful in identifying additional lead molecules to explore as PET imaging agents to visualize HDAC enzymes in vivo. However, HDACi brain penetrance predicted by LC-MS-MS did not strongly correlate with PET imaging results. This underscores the importance of in vivo PET imaging tools in characterizing putative CNS drug lead compounds and the continued need to discover effect PET tracers for neuroepigenetic imaging. PMID:24380043

Wang, Changning; Eessalu, Thomas E; Barth, Vanessa N; Mitch, Charles H; Wagner, Florence F; Hong, Yijia; Neelamegam, Ramesh; Schroeder, Frederick A; Holson, Edward B; Haggarty, Stephen J; Hooker, Jacob M

2013-01-01

37

Selective histone deacetylase (HDAC) inhibition imparts beneficial effects in Huntington's disease mice: implications for the ubiquitin–proteasomal and autophagy systems  

PubMed Central

We previously demonstrated that the histone deacetylase (HDAC) inhibitor, 4b, which preferentially targets HDAC1 and HDAC3, ameliorates Huntington's disease (HD)-related phenotypes in different HD model systems. In the current study, we investigated extensive behavioral and biological effects of 4b in N171-82Q transgenic mice and further explored potential molecular mechanisms of 4b action. We found that 4b significantly prevented body weight loss, improved several parameters of motor function and ameliorated Huntingtin (Htt)-elicited cognitive decline in N171-82Q transgenic mice. Pathways analysis of microarray data from the mouse brain revealed gene networks involving post-translational modification, including protein phosphorylation and ubiquitination pathways, associated with 4b drug treatment. Using real-time qPCR analysis, we validated differential regulation of several genes in these pathways by 4b, including Ube2K, Ubqln, Ube2e3, Usp28 and Sumo2, as well as several other related genes. Additionally, 4b elicited increases in the expression of genes encoding components of the inhibitor of kappaB kinase (IKK) complex. IKK activation has been linked to phosphorylation, acetylation and clearance of the Htt protein by the proteasome and the lysosome, and accordingly, we found elevated levels of phosphorylated endogenous wild-type (wt) Htt protein at serine 16 and threonine 3, and increased AcK9/pS13/pS16 immunoreactivity in cortical samples from 4b-treated mice. We further show that HDAC inhibitors prevent the formation of nuclear Htt aggregates in the brains of N171-82Q mice. Our findings suggest that one mechanism of 4b action is associated with the modulation of the ubiquitin–proteasomal and autophagy pathways, which could affect accumulation, stability and/or clearance of important disease-related proteins, such as Htt. PMID:22965876

Jia, Haiqun; Kast, Ryan J.; Steffan, Joan S.; Thomas, Elizabeth A.

2012-01-01

38

Structure, Mechanism, and Inhibition of Histone Deacetylases and Related Metalloenzymes  

PubMed Central

Metal-dependent histone deacetylases (HDACs) catalyze the hydrolysis of acetyl-L-lysine side chains in histone and non-histone proteins to yield L-lysine and acetate. This chemistry plays a critical role in the regulation of numerous biological processes. Aberrant HDAC activity is implicated in various diseases, and HDACs are validated targets for drug design. Two HDAC inhibitors are currently approved for cancer chemotherapy, and other inhibitors are in clinical trials. To date, X-ray crystal structures are available for four human HDACs (2, 4, 7, 8) and three HDAC-related deacetylases from bacteria (histone deacetylase-like protein, HDLP; histone deacetylase-like amidohydrolase, HDAH; acetylpolyamine amidohydrolase, APAH). Structural comparisons among these enzymes reveal a conserved constellation of active site residues, suggesting a common mechanism for the metal-dependent hydrolysis of acetylated substrates. Structural analyses of HDACs and HDAC-related deacetylases guide the design of tight-binding inhibitors, and future prospects for developing isozyme-specific inhibitors are quite promising. PMID:21872466

Lombardi, Patrick M.; Cole, Kathryn E.; Dowling, Daniel P.; Christianson, David W.

2011-01-01

39

Deacetylase-Independent Function of HDAC3 in Transcription and Metabolism Requires Nuclear Receptor Corepressor  

PubMed Central

Histone deacetylases (HDACs) are believed to regulate gene transcription by catalyzing deacetylation reactions. HDAC3 depletion in mouse liver upregulates lipogenic genes and results in severe hepatosteatosis. Here we show that pharmacologic HDAC inhibition in primary hepatocytes causes histone hyperacetylation but does not upregulate expression of HDAC3 target genes. Meanwhile, deacetylase-dead HDAC3 mutants can rescue hepatosteatosis and repress lipogenic genes expression in HDAC3-depleted mouse liver, demonstrating that histone acetylation is insufficient to activate gene transcription. Mutations abolishing interactions with the nuclear receptor corepressor (NCOR or SMRT) render HDAC3 nonfunctional in vivo. Additionally, liver-specific knockout of NCOR, but not SMRT, causes metabolic and transcriptomal alterations resembling those of mice without hepatic HDAC3, demonstrating that interaction with NCOR is essential for deacetylase-independent function of HDAC3. These findings highlight non-enzymatic roles of a major HDAC in transcriptional regulation in vivo and warrant reconsideration of the mechanism of action of HDAC inhibitors. PMID:24268577

Sun, Zheng; Feng, Dan; Fang, Bin; Mullican, Shannon E.; You, Seo-Hee; Lim, Hee-Woong; Everett, Logan J.; Nabel, Christopher S.; Li, Yun; Selvakumaran, Vignesh; Won, Kyoung-Jae; Lazar, Mitchell A.

2013-01-01

40

Post-Training Intrahippocampal Inhibition of Class I Histone Deacetylases Enhances Long-Term Object-Location Memory  

ERIC Educational Resources Information Center

Long-term memory formation involves covalent modification of the histone proteins that package DNA. Reducing histone acetylation by mutating histone acetyltransferases impairs long-term memory, and enhancing histone acetylation by inhibiting histone deacetylases (HDACs) improves long-term memory. Previous studies using HDAC inhibitors to enhance…

Hawk, Joshua D.; Florian, Cedrick; Abel, Ted

2011-01-01

41

Inhibition of class II histone deacetylases in the spinal cord attenuates inflammatory hyperalgesia  

Microsoft Academic Search

BACKGROUND: Several classes of histone deacetylases (HDACs) are expressed in the spinal cord that is a critical structure of the nociceptive pathway. HDAC-regulated histone acetylation is an important component of chromatin remodeling leading to epigenetic regulation of gene transcription. To understand the role of histone acetylation in epigenetic regulation of pathological pain, we have studied the impact of different classes

Guang Bai; Dong Wei; Shiping Zou; Ke Ren; Ronald Dubner

2010-01-01

42

Inhibition of histone deacetylase 10 induces thioredoxin-interacting protein and causes accumulation of reactive oxygen species in SNU-620 human gastric cancer cells  

Microsoft Academic Search

Histone deacetylase (HDAC)10, a novel class IIb histone deacetylase, is the most similar to HDAC6, since both contain a unique\\u000a second catalytic domain. Unlike HDAC6, which is located in the cytoplasm, HDAC10 resides in both the nucleus and cytoplasm.\\u000a The transcriptional targets of HDAC10 that are associated with HDAC10 gene regulation have not been identified. In the present\\u000a study, we

Ju-Hee Lee; Eun-Goo Jeong; Moon-Chang Choi; Sung-Hak Kim; Jung-Hyun Park; Sang-Hyun Song; Jinah Park; Yung-Jue Bang; Tae-You Kim

2010-01-01

43

Histone deacetylase inhibitors in the treatment of lymphoma.  

PubMed

Histone deacetylases (HDACs) play an important role in the regulation of gene expression. In addition to histones, HDACs can modulate the function of many other proteins involved in the regulation of cell survival and proliferation, angiogenesis, inflammation, and immunity. Deregulated HDACs have been shown to be commonly associated with many types of cancer, and are considered promising targets for cancer therapy. Several HDAC inhibitors are in clinical trials as monotherapies or in combination with other anticancer agents, but only two such inhibitors -- vorinostat (suberoylanilide hydroxamic acid) and romidepsin (depsipeptide) -- have been approved by the US Food and Drug Administration for treating relapsed cutaneous T-cell lymphoma. Other HDAC inhibitors, such as belinostat (PXD101), mocetinostat (MGCD0103), entinostat (SNDX-275), and panobinostat (LBH589), are currently in clinical development. This review focuses on the use of HDAC inhibitors in the treatment of relapsed lymphoma. PMID:21122478

Lemoine, Manuela; Younes, Anas

2010-11-01

44

Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors.  

PubMed

The human HDAC (histone deacetylase) family, a well-validated anticancer target, plays a key role in the control of gene expression through regulation of transcription. While HDACs can be subdivided into three main classes, the class I, class II and class III HDACs (sirtuins), it is presently unclear whether inhibiting multiple HDACs using pan-HDAC inhibitors, or targeting specific isoforms that show aberrant levels in tumours, will prove more effective as an anticancer strategy in the clinic. To address the above issues, we have tested a number of clinically relevant HDACis (HDAC inhibitors) against a panel of rhHDAC (recombinant human HDAC) isoforms. Eight rhHDACs were expressed using a baculoviral system, and a Fluor de Lystrade mark (Biomol International) HDAC assay was optimized for each purified isoform. The potency and selectivity of ten HDACs on class I isoforms (rhHDAC1, rhHDAC2, rhHDAC3 and rhHDAC8) and class II HDAC isoforms (rhHDAC4, rhHDAC6, rhHDAC7 and rhHDAC9) was determined. MS-275 was HDAC1-selective, MGCD0103 was HDAC1- and HDAC2-selective, apicidin was HDAC2- and HDAC3-selective and valproic acid was a specific inhibitor of class I HDACs. The hydroxamic acid-derived compounds (trichostatin A, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat) were potent pan-HDAC inhibitors. The growth-inhibitory effect of the HDACis on HeLa cells showed that both pan-HDAC and class-I-specific inhibitors inhibited cell growth. The results also showed that both pan-HDAC and class-I-specific inhibitor treatment resulted in increased acetylation of histones, but only pan-HDAC inhibitor treatment resulted in increased tubulin acetylation, which is in agreement with their activity towards the HDAC6 isoform. PMID:17868033

Khan, Nagma; Jeffers, Michael; Kumar, Sampath; Hackett, Craig; Boldog, Ferenc; Khramtsov, Nicholai; Qian, Xiaozhong; Mills, Evan; Berghs, Stanny C; Carey, Nessa; Finn, Paul W; Collins, Laura S; Tumber, Anthony; Ritchie, James W; Jensen, Peter Buhl; Lichenstein, Henri S; Sehested, Maxwell

2008-01-15

45

The Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid Induces Apoptosis via Induction of 15Lipoxygenase1 in Colorectal Cancer Cells  

Microsoft Academic Search

Histone deacetylases (HDACs) mediate changes in nucleosome confor- mation and are important in the regulation of gene expression. HDACs are involved in cell cycle progression and differentiation, and their dereg- ulation is associated with several cancers. HDAC inhibitors have emerged recently as promising chemotherapeutic agents. One such agent, suberoy- lanilide hydroxamic acid, is a potent inhibitor of HDACs that causes

Linda C. Hsi; Xiaopei Xi; Reuben Lotan; Imad Shureiqi; Scott M. Lippman

2004-01-01

46

Histone Deacetylase 5 Limits Cocaine Reward through cAMP-Induced Nuclear Import  

E-print Network

Chromatin remodeling by histone deacetylases (HDACs) is a key mechanism regulating behavioral adaptations to cocaine use. We report here that cocaine and cyclic adenosine monophosphate (cAMP) signaling induce the transient ...

Taniguchi, Makoto

47

Histone deacetylase induces accelerated maturation in Xenopus laevis oocytes.  

PubMed

In oocyte maturation in Xenopus laevis, nuclear material induces rapid maturation and is required for entry into meiosis II. Nuclear material contains a large number of RNAs and proteins, including histone deacetylase (HDAC); however, it is not known which materials induce accelerated maturation. The HDAC activity modifies transcription rate and is required for normal meiosis; however, its function in oocyte maturation is still unclear. We investigated the function of HDAC activity, which is localized in the nuclear material, in the regulation of the speed of oocyte maturation. Inhibition of HDAC activity with trichostatin A (TSA) induced hyperacetylation of histone H3 and prolonged oocyte maturation. In contrast, increase in HDAC activity with an injection of FLAG-tagged maternal histone deacetylase (HDACm-FLAG) mRNA induced deacetylation of histone H3 and reduced the duration of oocyte maturation. Cdc2 kinase, Cdc25C or mitogen-activated protein kinase (MAPK), which are key regulators of the meiosis, were activated coincidently with maturation progression. In oocytes, the mRNA level of Cdc25C, an activator of Cdc2, was increased by HDACm-FLAG mRNA-injection; in contrast, the mRNA level of Cdc2 inhibitor Wee1 was increased by TSA treatment. These results suggest that HDAC activity is involved in the control of maturation speed through the regulation of mRNA levels of cell cycle regulators. Thus, HDACm is a candidate for the nuclear material component that induces rapid maturation in Xenopus oocytes. PMID:23346879

Iwashita, Jun; Kodama, Ayumi; Konno, Yuuri; Abe, Tatsuya; Murata, Jun

2013-04-01

48

New Endogenous Regulators of Class I Histone Deacetylases  

NSDL National Science Digital Library

Gene expression in eukaryotes depends on epigenetic changes that occur on both histones and DNA. Class I histone deacetylases (HDACs) are enzymes that remove acetyl groups from histones and other nuclear proteins, thereby inducing chromatin condensation and transcriptional repression. HDACs belong to a large family of enzymes that undergo posttranslational modifications after the activation of several intracellular pathways. However, the environmental stimuli that change nuclear HDAC functions remain largely unknown. New evidence has demonstrated that the lipid sphingosine-1-phosphate (S1P) inhibits the activity of HDAC1 and HDAC2. Both S1P and sphingosine kinase 2 (SphK2), the enzyme that synthesizes S1P, are assembled in corepressor complexes containing HDAC1 and HDAC2. S1P is among the few endogenous HDAC inhibitors that is synthesized in the nucleus in response to extracellular stimulation, and the first nuclear lipid associated with an epigenetic modification. The discovery of endogenous molecules that regulate HDAC activity in vivo has implications for the development of new therapeutic approaches for a host of human diseases, including cancer and neurodegenerative disorders.

Antonella Riccio (University College London; MRC Laboratory for Molecular and Cell Biology REV)

2010-01-05

49

Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer  

Microsoft Academic Search

Histone deacetylases (HDACs) are considered to be among the most promising targets in drug development for cancer therapy, and first-generation histone deacetylase inhibitors (HDACi) are currently being tested in phase I\\/II clinical trials. A wide-ranging knowledge of the role of HDACs in tumorigenesis, and of the action of HDACi, has been achieved. However, several basic aspects are not yet fully

Pier Giuseppe Pelicci; Saverio Minucci

2006-01-01

50

Histone deacetylase inhibitors as potential treatment for spinal muscular atrophy  

PubMed Central

Histone acetylation plays an important role in regulation of transcription in eukaryotic cells by promoting a more relaxed chromatin structure necessary for transcriptional activation. Histone deacetylases (HDACs) remove acetyl groups and suppress gene expression. HDAC inhibitors (HDACIs) are a group of small molecules that promote gene transcription by chromatin remodeling and have been extensively studied as potential drugs for treating of spinal muscular atrophy. Various drugs in this class have been studied with regard to their efficacy in increasing the expression of survival of motor neuron (SMN) protein. In this review, we discuss the current literature on this topic and summarize the findings of the main studies in this field. PMID:24130434

Mohseni, Jafar; Zabidi-Hussin, Z.A.M.H.; Sasongko, Teguh Haryo

2013-01-01

51

Potent Antimalarial Activity of Histone Deacetylase Inhibitor Analogues? †  

PubMed Central

The malaria parasite Plasmodium falciparum has at least five putative histone deacetylase (HDAC) enzymes, which have been proposed as new antimalarial drug targets and may play roles in regulating gene transcription, like the better-known and more intensively studied human HDACs (hHDACs). Fourteen new compounds derived from l-cysteine or 2-aminosuberic acid were designed to inhibit P. falciparum HDAC-1 (PfHDAC-1) based on homology modeling with human class I and class II HDAC enzymes. The compounds displayed highly potent antiproliferative activity against drug-resistant (Dd2) or drug sensitive (3D7) strains of P. falciparum in vitro (50% inhibitory concentration of 13 to 334 nM). Unlike known hHDAC inhibitors, some of these new compounds were significantly more toxic to P. falciparum parasites than to mammalian cells. The compounds inhibited P. falciparum growth in erythrocytes at both the early and late stages of the parasite's life cycle and caused altered histone acetylation patterns (hyperacetylation), which is a marker of HDAC inhibition in mammalian cells. These results support PfHDAC enzymes as being promising targets for new antimalarial drugs. PMID:18212103

Andrews, K. T.; Tran, T. N.; Lucke, A. J.; Kahnberg, P.; Le, G. T.; Boyle, G. M.; Gardiner, D. L.; Skinner-Adams, T. S.; Fairlie, D. P.

2008-01-01

52

SQSTM1/p62 Interacts with HDAC6 and Regulates Deacetylase Activity  

PubMed Central

Protein aggregates can form in the cytoplasm of the cell and are accumulated at aggresomes localized to the microtubule organizing center (MTOC) where they are subsequently degraded by autophagy. In this process, aggregates are engulfed into autophagosomes which subsequently fuse with lysosomes for protein degradation. A member of the class II histone deacetylase family, histone deacetylase 6(HDAC6) has been shown to be involved in both aggresome formation and the fusion of autophagosomes with lysosomes making it an attractive target to regulate protein aggregation. The scaffolding protein sequestosome 1(SQSTM1)/p62 has also been shown to regulate accumulation and autophagic clearance of protein aggregates. Recent studies have revealed colocalization of HDAC6 and p62 to ubiquitinated mitochondria, as well as, ubiquitinated protein aggregates associated with the E3 ubiquitin ligase TRIM50. HDAC6 deacetylase activity is required for aggresome formation and can be regulated by protein interaction with HDAC6. Due to their colocalization at ubiquitinated protein aggregates, we sought to examine if p62 specifically interacted with HDAC6 and if so, if this interaction had any effect on HDAC6 activity and/or the physiological function of cortactin-F-actin assembly. We succeeded in identifying and mapping the direct interaction between HDAC6 and p62. We further show that this interaction regulates HDAC6 deacetylase activity. Data are presented demonstrating that the absence of p62 results in hyperactivation of HDAC6 and deacetylation of ?-tubulin and cortactin. Further, upon induction of protein misfolding we show that p62 is required for perinuclear co-localization of cortactin-F-actin assemblies. Thus, our findings indicate that p62 plays a key role in regulating the recruitment of F-actin network assemblies to the MTOC, a critical cellular function that is required for successful autophagic clearance of protein aggregates. PMID:24086678

Yan, Jin; Seibenhener, Michael Lamar; Calderilla-Barbosa, Luis; Diaz-Meco, Maria-Theresa; Moscat, Jorge; Jiang, Jianxiong; Wooten, Marie W.; Wooten, Michael C.

2013-01-01

53

Beyond Histone and Deacetylase: An Overview of Cytoplasmic Histone Deacetylases and Their Nonhistone Substrates  

PubMed Central

Acetylation of lysines is a prominent form of modification in mammalian proteins. Deacetylation of proteins is catalyzed by histone deacetylases, traditionally named after their role in histone deacetylation, transcriptional modulation, and epigenetic regulation. Despite the link between histone deacetylases and chromatin structure, some of the histone deacetylases reside in various compartments in the cytoplasm. Here, we review how these cytoplasmic histone deacetylases are regulated, the identification of nonhistone substrates, and the functional implications of their nondeacetylase enzymatic activities. PMID:21234400

Yao, Ya-Li; Yang, Wen-Ming

2011-01-01

54

Interpreting clinical assays for histone deacetylase inhibitors  

PubMed Central

As opposed to genetics, dealing with gene expressions by direct DNA sequence modifications, the term epigenetics applies to all the external influences that target the chromatin structure of cells with impact on gene expression unrelated to the sequence coding of DNA itself. In normal cells, epigenetics modulates gene expression through all development steps. When “imprinted” early by the environment, epigenetic changes influence the organism at an early stage and can be transmitted to the progeny. Together with DNA sequence alterations, DNA aberrant cytosine methylation and microRNA deregulation, epigenetic modifications participate in the malignant transformation of cells. Their reversible nature has led to the emergence of the promising field of epigenetic therapy. The efforts made to inhibit in particular the epigenetic enzyme family called histone deacetylases (HDACs) are described. HDAC inhibitors (HDACi) have been proposed as a viable clinical therapeutic approach for the treatment of leukemia and solid tumors, but also to a lesser degree for noncancerous diseases. Three epigenetic drugs are already arriving at the patient’s bedside, and more than 100 clinical assays for HDACi are registered on the National Cancer Institute website. They explore the eventual additive benefits of combined therapies. In the context of the pleiotropic effects of HDAC isoforms, more specific HDACi and more informative screening tests are being developed for the benefit of the patients. PMID:21625397

Martinet, Nadine; Bertrand, Philippe

2011-01-01

55

Histone deacetylase activities are required for innate immune cell control of Th1 but not Th2 effector cell function  

Microsoft Academic Search

Histone deacetylases (HDACs) play a criti- cal role in regulating gene expression and key biological processes. However, how HDACs are involved in innate immu- nity is little understood. Here, in this first systematic investigation of the role of HDACs in immunity, we show that HDAC inhibition by a small-molecule HDAC in- hibitor (HDACi), LAQ824, alters Toll-like receptor 4 (TLR4)-dependent activation

Jennifer L. Brogdon; Yongyao Xu; Susanne J. Szabo; Shaojian An; Francis Buxton; Dalia Cohen; Qian Huang

2007-01-01

56

HOS2 and HDA1 Encode Histone Deacetylases with Opposing Roles in Candida albicans Morphogenesis  

Microsoft Academic Search

Epigenetic mechanisms regulate the expression of virulence traits in diverse pathogens, including protozoan and fungi. In the human fungal pathogen Candida albicans, virulence traits such as antifungal resistance, white-opaque switching, and adhesion to lung cells are regulated by histone deacetylases (HDACs). However, the role of HDACs in the regulation of the yeast-hyphal morphogenetic transitions, a critical virulence attribute of C.

Lucia F. Zacchi; Wade L. Schulz; Dana A. Davis

2010-01-01

57

Class IIa Histone Deacetylases Are Conserved Regulators of Circadian Function*  

PubMed Central

Class IIa histone deacetylases (HDACs) regulate the activity of many transcription factors to influence liver gluconeogenesis and the development of specialized cells, including muscle, neurons, and lymphocytes. Here, we describe a conserved role for class IIa HDACs in sustaining robust circadian behavioral rhythms in Drosophila and cellular rhythms in mammalian cells. In mouse fibroblasts, overexpression of HDAC5 severely disrupts transcriptional rhythms of core clock genes. HDAC5 overexpression decreases BMAL1 acetylation on Lys-537 and pharmacological inhibition of class IIa HDACs increases BMAL1 acetylation. Furthermore, we observe cyclical nucleocytoplasmic shuttling of HDAC5 in mouse fibroblasts that is characteristically circadian. Mutation of the Drosophila homolog HDAC4 impairs locomotor activity rhythms of flies and decreases period mRNA levels. RNAi-mediated knockdown of HDAC4 in Drosophila clock cells also dampens circadian function. Given that the localization of class IIa HDACs is signal-regulated and influenced by Ca2+ and cAMP signals, our findings offer a mechanism by which extracellular stimuli that generate these signals can feed into the molecular clock machinery. PMID:25271152

Fogg, Paul C. M.; O'Neill, John S.; Dobrzycki, Tomasz; Calvert, Shaun; Lord, Emma C.; McIntosh, Rebecca L. L.; Elliott, Christopher J. H.; Sweeney, Sean T.; Hastings, Michael H.; Chawla, Sangeeta

2014-01-01

58

Identification and characterization of histone deacetylases in tomato (Solanum lycopersicum)  

PubMed Central

Histone acetylation and deacetylation at the N-terminus of histone tails play crucial roles in the regulation of eukaryotic gene activity. Histone acetylation and deacetylation are catalyzed by histone acetyltransferases and histone deacetylases (HDACs), respectively. A growing number of studies have demonstrated the importance of histone deacetylation/acetylation on genome stability, transcriptional regulation, development and response to stress in Arabidopsis. However, the biological functions of HDACs in tomato have not been investigated previously. Fifteen HDACs identified from tomato (Solanum lycopersicum) can be grouped into RPD3/HDA1, SIR2 and HD2 families based on phylogenetic analysis. Meanwhile, 10 members of the RPD3/HDA1 family can be further subdivided into four groups, namely Class I, Class II, Class III, and Class IV. High similarities of protein sequences and conserved domains were identified among SlHDACs and their homologs in Arabidopsis. Most SlHDACs were expressed in all tissues examined with different transcript abundance. Transient expression in Arabidopsis protoplasts showed that SlHDA8, SlHDA1, SlHDA5, SlSRT1 and members of the HD2 family were localized to the nucleus, whereas SlHDA3 and SlHDA4 were localized in both the cytoplasm and nucleus. The difference in the expression patterns and subcellular localization of SlHDACs suggest that they may play distinct functions in tomato. Furthermore, we found that three members of the RPD3/HDA1 family, SlHDA1, SIHDA3 and SlHDA4, interacted with TAG1 (TOMATO AGAMOUS1) and TM29 (TOMATO MADS BOX29), two MADS-box proteins associated with tomato reproductive development, indicating that these HDACs may be involved in gene regulation in reproductive development. PMID:25610445

Zhao, Linmao; Lu, Jingxia; Zhang, Jianxia; Wu, Pei-Ying; Yang, Songguang; Wu, Keqiang

2015-01-01

59

Valproic Acid (VPA), a Histone Deacetylase (HDAC) Inhibitor, Diminishes Lymphoproliferation in the Fas Deficient MRL/lpr?/? Murine Model of Autoimmune Lymphoproliferative Syndrome (ALPS)  

PubMed Central

Objective Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of apoptosis, often presenting in childhood. Similarly, MRL/lpr?/? mice homozygous for Fas mutations develop an ALPS-like disease with autoimmunity, lymphadenopathy, splenomegaly, and expansion of double negative T (DNT) cells. Currently, there are no proven therapies with adequate safety margins for sustained abolition of the lymphoproliferation associated with ALPS. We sought to test the ability of valproic acid (VPA), a histone deacetylase inhibitor, to induce apoptosis and inhibit lymphoproliferation. Methods Human peripheral blood mononuclear cells (PBMCs) from patients with ALPS and normal controls were tested in vitro to determine the efficacy of VPA at inducing cell death. VPA was used in vivo to control lymphoproliferation in MRL/lpr?/? mice, a model for ALPS. Results VPA induced cell death in vitro, and was partially inhibited by the pan caspase inhibitor, Z-VAD-FMK. MRL/lpr?/? mice treated with VPA for 8 weeks showed significant reductions in spleen and lymph node weights and cellularity compared to controls. A concomitant decrease in DNT cells was observed in the spleen, lymph nodes, and peripheral blood. Serum levels of VPA peaked 1 hour after injection, and a 2.5 fold increase in histone acetylation was observed in the spleen at 4 hours after injection. Conclusion Based on our data, VPA is effective at reducing lymphoproliferation in mice, and is currently being studied in a clinical trial as a lympholytic agent in patients with ALPS. PMID:19217201

Dowdell, Kennichi C; Pesnicak, Lesley; Hoffmann, Victoria; Steadman, Kenneth; Remaley, Alan T.; Cohen, Jeffrey I.; Straus, Stephen E; Rao, V. Koneti

2009-01-01

60

Targeting Histone Deacetylases: A Novel Approach in Parkinson's Disease  

PubMed Central

The worldwide prevalence of movement disorders is increasing day by day. Parkinson's disease (PD) is the most common movement disorder. In general, the clinical manifestations of PD result from dysfunction of the basal ganglia. Although the exact underlying mechanisms leading to neural cell death in this disease remains unknown, the genetic causes are often established. Indeed, it is becoming increasingly evident that chromatin acetylation status can be impaired during the neurological disease conditions. The acetylation and deacetylation of histone proteins are carried out by opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. In the recent past, studies with HDAC inhibitors result in beneficial effects in both in vivo and in vitro models of PD. Various clinical trials have also been initiated to investigate the possible therapeutic potential of HDAC inhibitors in patients suffering from PD. The possible mechanisms assigned for these neuroprotective actions of HDAC inhibitors involve transcriptional activation of neuronal survival genes and maintenance of histone acetylation homeostasis, both of which have been shown to be dysregulated in PD. In this review, the authors have discussed the putative role of HDAC inhibitors in PD and associated abnormalities and suggest new directions for future research in PD.

Sharma, Sorabh; Taliyan, Rajeev

2015-01-01

61

Targeting macrophage Histone deacetylase 3 stabilizes atherosclerotic lesions  

PubMed Central

Macrophages are key immune cells found in atherosclerotic plaques and critically shape atherosclerotic disease development. Targeting the functional repertoire of macrophages may hold novel approaches for future atherosclerosis management. Here, we describe a previously unrecognized role of the epigenomic enzyme Histone deacetylase 3 (Hdac3) in regulating the atherosclerotic phenotype of macrophages. Using conditional knockout mice, we found that myeloid Hdac3 deficiency promotes collagen deposition in atherosclerotic lesions and thus induces a stable plaque phenotype. Also, macrophages presented a switch to anti-inflammatory wound healing characteristics and showed improved lipid handling. The pro-fibrotic phenotype was directly linked to epigenetic regulation of the Tgfb1 locus upon Hdac3 deletion, driving smooth muscle cells to increased collagen production. Moreover, in humans, HDAC3 was the sole Hdac upregulated in ruptured atherosclerotic lesions, Hdac3 associated with inflammatory macrophages, and HDAC3 expression inversely correlated with pro-fibrotic TGFB1 expression. Collectively, we show that targeting the macrophage epigenome can improve atherosclerosis outcome and we identify Hdac3 as a potential novel therapeutic target in cardiovascular disease. PMID:25007801

Hoeksema, Marten A; Gijbels, Marion JJ; Van den Bossche, Jan; van der Velden, Saskia; Sijm, Ayestha; Neele, Annette E; Seijkens, Tom; Stöger, J Lauran; Meiler, Svenja; Boshuizen, Marieke CS; Dallinga-Thie, Geesje M; Levels, Johannes HM; Boon, Louis; Mullican, Shannon E; Spann, Nathanael J; Cleutjens, Jack P; Glass, Chris K; Lazar, Mitchell A; de Vries, Carlie JM; Biessen, Erik AL; Daemen, Mat JAP; Lutgens, Esther; de Winther, Menno PJ

2014-01-01

62

Histone deacetylase 10 promotes autophagy-mediated cell survival  

PubMed Central

Tumor cells activate autophagy in response to chemotherapy-induced DNA damage as a survival program to cope with metabolic stress. Here, we provide in vitro and in vivo evidence that histone deacetylase (HDAC)10 promotes autophagy-mediated survival in neuroblastoma cells. We show that both knockdown and inhibition of HDAC10 effectively disrupted autophagy associated with sensitization to cytotoxic drug treatment in a panel of highly malignant V-MYC myelocytomatosis viral-related oncogene, neuroblastoma derived-amplified neuroblastoma cell lines, in contrast to nontransformed cells. HDAC10 depletion in neuroblastoma cells interrupted autophagic flux and induced accumulation of autophagosomes, lysosomes, and a prominent substrate of the autophagic degradation pathway, p62/sequestosome 1. Enforced HDAC10 expression protected neuroblastoma cells against doxorubicin treatment through interaction with heat shock protein 70 family proteins, causing their deacetylation. Conversely, heat shock protein 70/heat shock cognate 70 was acetylated in HDAC10-depleted cells. HDAC10 expression levels in high-risk neuroblastomas correlated with autophagy in gene-set analysis and predicted treatment success in patients with advanced stage 4 neuroblastomas. Our results demonstrate that HDAC10 protects cancer cells from cytotoxic agents by mediating autophagy and identify this HDAC isozyme as a druggable regulator of advanced-stage tumor cell survival. Moreover, these results propose a promising way to considerably improve treatment response in the neuroblastoma patient subgroup with the poorest outcome. PMID:23801752

Oehme, Ina; Linke, Jan-Peter; Böck, Barbara C.; Milde, Till; Lodrini, Marco; Hartenstein, Bettina; Wiegand, Inga; Eckert, Christian; Roth, Wilfried; Kool, Marcel; Kaden, Sylvia; Gröne, Hermann-Josef; Schulte, Johannes H.; Lindner, Sven; Hamacher-Brady, Anne; Brady, Nathan R.; Deubzer, Hedwig E.; Witt, Olaf

2013-01-01

63

Metabolism as a key to histone deacetylase inhibition  

PubMed Central

There is growing interest in the epigenetic mechanisms that are dysregulated in cancer and other human pathologies. Under this broad umbrella, modulators of histone deacetylase (HDAC) activity have gained interest as both cancer chemopreventive and therapeutic agents. Of the first generation, FDA-approved HDAC inhibitors to have progressed to clinical trials, vorinostat represents a “direct acting” compound with structural features suitable for docking into the HDAC pocket, whereas romidepsin can be considered a prodrug that undergoes reductive metabolism to generate the active intermediate (a zinc-binding thiol). It is now evident that other agents, including those in the human diet, can be converted by metabolism to intermediates that affect HDAC activity. Examples are cited of short-chain fatty acids, seleno-?-keto acids, small molecule thiols, mercapturic acid metabolites, indoles, and polyphenols. The findings are discussed in the context of putative endogenous HDAC inhibitors generated by intermediary metabolism (e.g. pyruvate), the yin–yang of HDAC inhibition versus HDAC activation, and the screening assays that might be most appropriate for discovery of novel HDAC inhibitors in the future. PMID:21599534

Rajendran, Praveen; Williams, David E.; Ho, Emily; Dashwood, Roderick H.

2012-01-01

64

Synthesis and Structure Activity Relationship of 3-Hydroxypyridin-2-thione Based Histone Deacetylase Inhibitors  

PubMed Central

We have previously identified 3-hydroxypyridin-2-thione (3HPT) as a novel zinc binding group for histone deacetylase (HDAC) inhibition. Early structure activity relationship (SAR) studies led to various small molecules possessing selective inhibitory activity against HDAC6 or HDAC8 but are devoid of HDAC1 inhibition. To further delineate the depth of the SAR of 3HPT-derived HDAC inhibitors (HDACi), we have extended the SAR studies to include the linker region and the surface recognition group to optimize the HDAC inhibition. The current efforts resulted in the identification of two lead compounds 10d and 14e with potent HDAC6 and HDAC8 activities, but that are inactive against HDAC1. These new HDACi possess anti-cancer activities against various cancer cell lines including Jurkat J-?1 against which SAHA and the previously disclosed 3HPT-derived HDACi were inactive. PMID:24304348

Sodji, Quaovi H.; Patil, Vishal; Kornacki, James R.; Mrksich, Milan; Oyelere, Adegboyega K.

2014-01-01

65

Histone deacetylase inhibitors—turning epigenic mechanisms of gene regulation into tools of therapeutic intervention in malignant and other diseases  

Microsoft Academic Search

Histone deacetylase inhibitors reside among the most promising targeted anticancer agents that are potent inducers of growth\\u000a arrest, differentiation, and\\/or apoptotic cell death of transformed cells. In October 2006, the US Food and Drug Administration\\u000a approved the first drug of this new class, vorinostat (1, Zolinza, Merck). Several histone deacetylase (HDAC) inhibitors more are in clinical trials. HDAC inhibitors have

Daniel Riester; Christian Hildmann; Andreas Schwienhorst

2007-01-01

66

Aurora B-dependent regulation of class IIa histone deacetylases by mitotic nuclear localization signal phosphorylation.  

PubMed

Class IIa histone deacetylases (HDACs 4/5/7/9) are transcriptional regulators with critical roles in cardiac disease and cancer. HDAC inhibitors are promising anticancer agents, and although they are known to disrupt mitotic progression, the underlying mechanisms of mitotic regulation by HDACs are not fully understood. Here we provide the first identification of histone deacetylases as substrates of Aurora B kinase (AurB). Our study identifies class IIa HDACs as a novel family of AurB targets and provides the first evidence that HDACs are temporally and spatially regulated by phosphorylation during the cell cycle. We define the precise site of AurB-mediated phosphorylation as a conserved serine within the nuclear localization signals of HDAC4, HDAC5, and HDAC9 at Ser265, Ser278, and Ser242, respectively. We establish that AurB interacts with these HDACs in vivo, and that this association increases upon disruption of 14-3-3 binding. We observe colocalization of endogenous, phosphorylated HDACs with AurB at the mitotic midzone in late anaphase and the midbody during cytokinesis, complemented by a reduction in HDAC interactions with components of the nuclear corepressor complex. We propose that AurB-dependent phosphorylation of HDACs induces sequestration within a phosphorylation gradient at the midzone, maintaining separation from re-forming nuclei and contributing to transcriptional control. PMID:22865920

Guise, Amanda J; Greco, Todd M; Zhang, Irene Y; Yu, Fang; Cristea, Ileana M

2012-11-01

67

Deletion of Histone Deacetylase 3 reveals critical roles in S-phase progression and DNA damage control  

PubMed Central

Histone deacetylases (HDAC) are enzymes that modify key residues in histones to regulate chromatin architecture, and play a vital role in cell survival, cell cycle progression, and tumorigenesis. To understand the function of Hdac3, a critical component of the N-CoR/SMRT repression complex, a conditional allele of Hdac3 was engineered. Cre-recombinase-mediated inactivation of Hdac3 led to a delay in cell cycle progression, cell-cycle dependent DNA damage, and apoptosis in mouse embryonic fibroblasts (MEFs). While no overt defects in mitosis were observed in Hdac3?/? MEFs, including normal H3Ser10 phosphorylation, DNA damage was observed in Hdac3?/?interphase cells, which appears to be associated with defective DNA double strand break repair. Moreover, we noted that Hdac3?/? MEFs were protected from DNA damage when quiescent, which may provide a mechanistic basis for the action of histone deacetylase inhibitors on cycling tumor cells. PMID:18406327

Bhaskara, Srividya; Chyla, Brenda J.; Amann, Joseph M.; Knutson, Sarah K.; Cortez, David; Sun, Zu-Wen; Hiebert, Scott W.

2008-01-01

68

Troglitazone inhibits histone deacetylase activity in breast cancer cells.  

PubMed

We previously demonstrated that the PPARgamma agonist Troglitazone (TRG), a potent antiproliferative agent, in combination with the anthracycline antibiotic Doxorubicin (DOX), is an effective killer of multiple drug resistant (MDR) human cancer cells. Cell killing was accompanied by increased global histone H3 acetylation. Presently, we investigated the epigenetic and cell killing effects of TRG in estrogen receptor (ER) positive MCF7 breast cancer cells. MCF7 cells were treated with the Thiazolidinediones (TZDs) TRG and Ciglitazone (CIG), the non-TZD PPARgamma agonist 15PGJ2, and the histone deacetylase inhibitors (HDACi's) Trichostatin A (TSA), sodium butyrate and PXD101. Using MTT cell viability assays, Western analyzes and mass spectrometry, we showed a dose-dependent increase in cell killing in TRG and HDACi treated cells, that was associated with increased H3 lysine 9 (H3K9) and H3K23 acetylation, H2AX and H3S10 phosphorylation, and H3K79 mono- and di-methylation. These effects were mediated through an ER independent pathway. Using HDAC activity assays, TRG inhibited HDAC activity in cells and in cell lysates, similar to that observed with TSA. Furthermore, TRG and TSA induced a slower migrating HDAC1 species that was refractory to HDAC2 associations. Lastly, TRG and the HDACi's decreased total and phosphorylated AKT levels. These findings suggest that TRG's mode of killing may involve downregulation of PI3K signaling through HDAC inhibition, leading to increased global histone post-translational modifications. PMID:19699029

Davies, G F; Ross, A R; Arnason, T G; Juurlink, B H J; Harkness, T A A

2010-02-28

69

Role of histone deacetylases in gene regulation at nuclear lamina.  

PubMed

Theoretical models suggest that gene silencing at the nuclear periphery may involve "closing" of chromatin by transcriptional repressors, such as histone deacetylases (HDACs). Here we provide experimental evidence confirming these predictions. Histone acetylation, chromatin compactness, and gene repression in lamina-interacting multigenic chromatin domains were analyzed in Drosophila S2 cells in which B-type lamin, diverse HDACs, and lamina-associated proteins were downregulated by dsRNA. Lamin depletion resulted in decreased compactness of the repressed multigenic domain associated with its detachment from the lamina and enhanced histone acetylation. Our data reveal the major role for HDAC1 in mediating deacetylation, chromatin compaction, and gene silencing in the multigenic domain, and an auxiliary role for HDAC3 that is required for retention of the domain at the lamina. These findings demonstrate the manifold and central involvement of class I HDACs in regulation of lamina-associated genes, illuminating a mechanism by which these enzymes can orchestrate normal and pathological development. PMID:23226217

Milon, Beatrice C; Cheng, Haibo; Tselebrovsky, Mikhail V; Lavrov, Sergei A; Nenasheva, Valentina V; Mikhaleva, Elena A; Shevelyov, Yuri Y; Nurminsky, Dmitry I

2012-01-01

70

Role of Histone Deacetylases in Gene Regulation at Nuclear Lamina  

PubMed Central

Theoretical models suggest that gene silencing at the nuclear periphery may involve “closing” of chromatin by transcriptional repressors, such as histone deacetylases (HDACs). Here we provide experimental evidence confirming these predictions. Histone acetylation, chromatin compactness, and gene repression in lamina-interacting multigenic chromatin domains were analyzed in Drosophila S2 cells in which B-type lamin, diverse HDACs, and lamina-associated proteins were downregulated by dsRNA. Lamin depletion resulted in decreased compactness of the repressed multigenic domain associated with its detachment from the lamina and enhanced histone acetylation. Our data reveal the major role for HDAC1 in mediating deacetylation, chromatin compaction, and gene silencing in the multigenic domain, and an auxiliary role for HDAC3 that is required for retention of the domain at the lamina. These findings demonstrate the manifold and central involvement of class I HDACs in regulation of lamina-associated genes, illuminating a mechanism by which these enzymes can orchestrate normal and pathological development. PMID:23226217

Milon, Beatrice C.; Cheng, Haibo; Tselebrovsky, Mikhail V.; Lavrov, Sergei A.; Nenasheva, Valentina V.; Mikhaleva, Elena A.; Shevelyov, Yuri Y.; Nurminsky, Dmitry I.

2012-01-01

71

Cloning, expression, and biochemical characterization of a new histone deacetylase-like protein from Thermus caldophilus GK24  

SciTech Connect

Histone deactylases (HDACs) are members of an ancient enzyme family found in eukaryotes as well as in prokaryotes such as archaebacteria and eubacteria. We here report a new histone deacetylase (Tca HDAC) that was cloned from the genomic library of Thermus caldophilus GK24 based on homology analysis with human histone deacetylase1 (HDAC1). The gene contains an open reading frame encoding 375 amino acids with a calculated molecular mass of 42,188 Da and the deduced amino acid sequence of Tca HDAC showed a 31% homology to human HDAC1. The Tca HDAC gene was over-expressed in Escherichia coli using a Glutathione-S transferase (GST) fusion vector (pGEX-4T-1) and the purified protein showed a deacetylase activity toward the fluorogenic substrate for HDAC. Moreover, the enzyme activity was inhibited by trichostatin A, a specific HDAC inhibitor, in a dose-dependent manner. Optimum temperature and pH of the enzyme was found to be approximately 70 {sup o}C and 7.0, respectively. In addition, zinc ion is required for catalytic activity of the enzyme. Together, these data demonstrate that Tca HDAC is a new histone deacetylase-like enzyme from T. caldophilus GK24 and will be a useful tool for deciphering the role of HDAC in the prokaryote and development of new biochemical reactions.

Song, Young Mi [Chemical Genomics Laboratory, Department of Biotechnology, College of Engineering, Yonsei University, Seoul 120-749 (Korea, Republic of); Kim, You Sun [Chemical Genomics Laboratory, Department of Biotechnology, College of Engineering, Yonsei University, Seoul 120-749 (Korea, Republic of); Kim, Dooil [Korea Research Institute of Bioscience and Biotechnology, Daejon 305-600 (Korea, Republic of); Lee, Dae Sil [Korea Research Institute of Bioscience and Biotechnology, Daejon 305-600 (Korea, Republic of); Kwon, Ho Jeong [Chemical Genomics Laboratory, Department of Biotechnology, College of Engineering, Yonsei University, Seoul 120-749 (Korea, Republic of)]. E-mail: kwonhj@yonsei.ac.kr

2007-09-14

72

Regulation of Immune Responses by Histone Deacetylase Inhibitors  

PubMed Central

Both genetic and epigenetic factors are important regulators of the immune system. There is an increasing body of evidence attesting to epigenetic modifications that influence the development of distinct innate and adaptive immune response cells. Chromatin remodelling via acetylation, methylation, phosphorylation, and ubiquitination of histone proteins as well as DNA, methylation is epigenetic mechanisms by which immune gene expression can be controlled. In this paper, we will discuss the role of epigenetics in the regulation of host immunity, with particular emphasis on histone deacetylase inhibitors. In particular, the role of HDAC inhibitors as a new class of immunomodulatory therapeutics will also be reviewed. PMID:22461998

Licciardi, Paul V.; Karagiannis, Tom C.

2012-01-01

73

How histone deacetylases control myelination.  

PubMed

Myelinated axons are a beautiful example of symbiotic interactions between two cell types: Myelinating glial cells organize axonal membranes and build their myelin sheaths to allow fast action potential conduction, while axons regulate myelination and enhance the survival of myelinating cells. Axonal demyelination, occurring in neurodegenerative diseases or after a nerve injury, results in severe motor and/or mental disabilities. Thus, understanding how the myelination process is induced, regulated, and maintained is crucial to develop new therapeutic strategies for regeneration in the nervous system. Epigenetic regulation has recently been recognized as a fundamental contributing player. In this review, we focus on the central mechanisms of gene regulation mediated by histone deacetylation and other key functions of histone deacetylases in Schwann cells and oligodendrocytes, the myelinating glia of the peripheral and central nervous systems. PMID:21861092

Jacob, Claire; Lebrun-Julien, Frédéric; Suter, Ueli

2011-12-01

74

Expression of histone deacetylases 1, 2 and 3 in urothelial bladder cancer  

PubMed Central

Background Histone deacetylases (HDACs) are known to be associated with an overexpression in different types of cancer such as colon and prostate cancer. In this study we aimed to evaluate the protein expression of class I HDACs in urothelial carcinoma of the bladder. Methods A tissue microarray containing 348 tissuesamples from 174 patients with a primary urothelial carcinoma of the bladder was immunohistochemically stained for HDAC 1, 2 and 3. Intensity of staining was evaluated and the association with clinico-pathological features and prognosis was assessed. Results High HDAC expression levels were found in 40 to 60% of all investigated urothelial carcinomas (HDAC-1: 40%, HDAC-2: 42%, HDAC-3: 59%). HDAC-1 and HDAC-2 were significantly associated with higher tumour grades. Although all three markers could not predict progression in univariate analyses, high HDAC-1 expression was associated with a trend toward poorer prognosis. Patients with high-grade tumours and high expression levels of HDAC-1 were more likely to progress compared to all other patients (p?HDAC-1 and HDAC-2. High grade tumours in combination with high expression of HDAC-1 showed a worse prognosis than the other tumours. The high expression levels of HDACs observed particularly in high grade urothelial bladder cancer clearly warrant subsequent studies on the potential use of HDAC inhibitors as a novel therapeutic approach. PMID:24624923

2014-01-01

75

Histone Deacetylase 3 orchestrates commensal bacteria-dependent intestinal homeostasis  

PubMed Central

The development and severity of inflammatory bowel diseases (IBD) and other chronic inflammatory conditions can be influenced by host genetic and environmental factors, including signals derived from commensal bacteria1–6. However, the mechanisms that integrate these diverse cues remain undefined. Here we demonstrate that mice with an intestinal epithelial cell-specific deletion of the epigenome-modifying enzyme histone deacetylase 3 (HDAC3?IEC mice) exhibited extensive dysregulation of IEC-intrinsic gene expression, including decreased basal expression of genes associated with antimicrobial defense. Critically, conventionally-housed HDAC3?IEC mice demonstrated loss of Paneth cells, impaired IEC function and alterations in the composition of intestinal commensal bacteria. In addition, HDAC3?IEC mice exhibited significantly increased susceptibility to intestinal damage and inflammation, indicating that epithelial expression of HDAC3 plays a central role in maintaining intestinal homeostasis. Rederivation of HDAC3?IEC mice into germ-free conditions revealed that dysregulated IEC gene expression, Paneth cell homeostasis, and intestinal barrier function were largely restored in the absence of commensal bacteria. While the specific mechanisms through which IEC-intrinsic HDAC3 expression regulates these complex phenotypes remain to be elucidated, these data indicate that HDAC3 is a critical factor that integrates commensal bacteria-derived signals to calibrate epithelial cell responses required to establish normal host-commensal relationships and maintain intestinal homeostasis. PMID:24185009

Alenghat, Theresa; Osborne, Lisa C.; Saenz, Steven A.; Kobuley, Dmytro; Ziegler, Carly G. K.; Mullican, Shannon E.; Choi, Inchan; Grunberg, Stephanie; Sinha, Rohini; Wynosky-Dolfi, Meghan; Snyder, Annelise; Giacomin, Paul R.; Joyce, Karen L.; Hoang, Tram B.; Bewtra, Meenakshi; Brodsky, Igor E.; Sonnenberg, Gregory F.; Bushman, Frederic D.; Won, Kyoung-Jae; Lazar, Mitchell A.; Artis, David

2014-01-01

76

Disruption of IkappaB kinase (IKK)-mediated RelA serine 536 phosphorylation sensitizes human multiple myeloma cells to histone deacetylase (HDAC) inhibitors.  

PubMed

Post-translational modifications of RelA play an important role in regulation of NF-?B activation. We previously demonstrated that in malignant hematopoietic cells, histone deacetylase inhibitors (HDACIs) induced RelA hyperacetylation and NF-?B activation, attenuating lethality. We now present evidence that I?B kinase (IKK) ?-mediated RelA Ser-536 phosphorylation plays a significant functional role in promoting RelA acetylation, inducing NF-?B activation, and limiting HDACI lethality in human multiple myeloma (MM) cells. Immunoblot profiling revealed that although basal RelA phosphorylation varied in MM cells, Ser-536 phosphorylation correlated with IKK activity. Exposure to the pan-HDACIs vorinostat or LBH-589 induced phosphorylation of IKK?/? (Ser-180/Ser-181) and RelA (Ser-536) in MM cells, including cells expressing an I?B? "super-repressor," accompanied by increased RelA nuclear translocation, acetylation, DNA binding, and transactivation activity. These events were substantially blocked by either pan-IKK or IKK?-selective inhibitors, resulting in marked apoptosis. Consistent with these events, inhibitory peptides targeting either the NF-?B essential modulator (NEMO) binding domain for IKK complex formation or RelA phosphorylation sites also significantly increased HDACI lethality. Moreover, IKK? knockdown by shRNA prevented Ser-536 phosphorylation and significantly enhanced HDACI susceptibility. Finally, introduction of a nonphosphorylatable RelA mutant S536A, which failed to undergo acetylation in response to HDACIs, impaired NF-?B activation and increased cell death. These findings indicate that HDACIs induce Ser-536 phosphorylation of the NF-?B subunit RelA through an IKK?-dependent mechanism, an action that is functionally involved in activation of the cytoprotective NF-?B signaling cascade primarily through facilitation of RelA acetylation rather than nuclear translocation. PMID:21816815

Dai, Yun; Chen, Shuang; Wang, Li; Pei, Xin-Yan; Funk, Vanessa L; Kramer, Lora B; Dent, Paul; Grant, Steven

2011-09-30

77

Histone deacetylase expression patterns in developing murine optic nerve  

PubMed Central

Background Histone deacetylases (HDACs) play important roles in glial cell development and in disease states within multiple regions of the central nervous system. However, little is known about HDAC expression or function within the optic nerve. As a first step in understanding the role of HDACs in optic nerve, this study examines the spatio-temporal expression patterns of methylated histone 3 (K9), acetylated histone 3 (K18), and HDACs 1–6 and 8–11 in the developing murine optic nerve head. Results Using RT-qPCR, western blot and immunofluorescence, three stages were analyzed: embryonic day 16 (E16), when astrocyte precursors are found in the optic stalk, postnatal day 5 (P5), when immature astrocytes and oligodendrocytes are found throughout the optic nerve, and P30, when optic nerve astrocytes and oligodendrocytes are mature. Acetylated and methylated histone H3 immunoreactivity was co-localized in the nuclei of most SOX2 positive glia within the optic nerve head and adjacent optic nerve at all developmental stages. HDACs 1–11 were expressed in the optic nerve glial cells at all three stages of optic nerve development in the mouse, but showed temporal differences in overall levels and subcellular localization. HDACs 1 and 2 were predominantly nuclear throughout optic nerve development and glial cell maturation. HDACs 3, 5, 6, 8, and 11 were predominantly cytoplasmic, but showed nuclear localization in at least one stage of optic nerve development. HDACs 4, 9 and10 were predominantly cytoplasmic, with little to no nuclear expression at any time during the developmental stages examined. Conclusions Our results showing that HDACs 1, 2, 3, 5, 6, 8, and 11 were each localized to the nuclei of SOX2 positive glia at some stages of optic nerve development and maturation and extend previous reports of HDAC expression in the aging optic nerve. These HDACs are candidates for further research to understand how chromatin remodeling through acetylation, deacetylation and methylation contributes to glial development as well as their injury response. PMID:25011550

2014-01-01

78

Functional characterization of Candida albicans Hos2 histone deacetylase  

PubMed Central

Candida albicans is a mucosal commensal organism capable of causing superficial (oral and vaginal thrush) infections in immune normal hosts, but is a major pathogen causing systemic and mucosal infections in immunocompromised individuals. Azoles have been very effective anti-fungal agents and the mainstay in treating opportunistic mold and yeast infections. Azole resistant strains have emerged compromising the utility of this class of drugs. It has been shown that azole resistance can be reversed by the co-administration of a histone deacetylase (HDAC) inhibitor, suggesting that resistance is mediated by epigenetic mechanisms possibly involving Hos2, a fungal deacetylase. We report here the cloning and functional characterization of  HOS2 (High Osmolarity  Sensitive) , a gene coding for fungal histone deacetylase from  C. albicans. Inhibition studies showed that Hos2 is susceptible to pan inhibitors such as trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), but is not inhibited by class I inhibitors such as MS-275. This  in  vitro enzymatic assay, which is amenable to high throughput could be used for screening potent fungal Hos2 inhibitors that could be a potential anti-fungal adjuvant. Purified Hos2 protein consistently deacetylated tubulins, rather than histones from TSA-treated cells. Hos2 has been reported to be a putative NAD+ dependent histone deacetylase, a feature of sirtuins. We assayed for sirtuin activation with resveratrol and purified Hos2 protein and did not find any sirtuin activity. PMID:25110576

Karthikeyan, G; Paul-Satyaseela, Maneesh; Dhatchana Moorthy, Nachiappan; Gopalaswamy, Radha; Narayanan, Shridhar

2014-01-01

79

Histone deacetylase inhibitors: apoptotic effects and clinical implications (Review).  

PubMed

It has been shown that epigenetic modifications play an important role in tumorigenesis. Thus, affecting epigenetic tumorigenic alterations can represent a promising strategy for anticancer targeted therapy. Among the key chromatin modifying enzymes which influence gene expression, histone acetyltransferases (HATs) and histone deacetylases (HDACs) have recently attracted interest because of their impact on tumor development and progression. Increased expression of HDACs and disrupted activities of HATs have been found in several tumor types, with a consequent hypoacetylated state of chromatin that can be strictly correlated with low expression of either tumor suppressor or pro-apoptotic genes. Histone deacetylase inhibitors (HDACIs) represent a new and promising class of antitumor drugs that influence gene expression by enhancing acetylation of histones in specific chromatin domains. HDACIs have been shown to exert potent anticancer activities inducing cell cycle arrest and apoptosis. Notably, a high efficacy of these drugs has been selectively revealed in malignant cells rather than in normal cells. Moreover, the therapeutic potential of these agents is also supported by the evidence that HDACIs downregulate genes involved in tumor progression, invasion and angiogenesis. Several HDACIs are currently under clinical investigation, including vorinostat (SAHA), romidepsin (depsipeptide, FK-228), LAQ824/LBH589 and belinostat (PXD101), compounds that have shown therapeutic potential in many types of malignancies including solid tumors. Based on the ability of HDACIs to regulate many signaling pathways, co-treatment of these compounds with molecular targeted drugs is a promising strategy against many types of tumors. PMID:18813776

Emanuele, Sonia; Lauricella, Marianna; Tesoriere, Giovanni

2008-10-01

80

Screening of selective histone deacetylase inhibitors by proteochemometric modeling  

PubMed Central

Background Histone deacetylase (HDAC) is a novel target for the treatment of cancer and it can be classified into three classes, i.e., classes I, II, and IV. The inhibitors selectively targeting individual HDAC have been proved to be the better candidate antitumor drugs. To screen selective HDAC inhibitors, several proteochemometric (PCM) models based on different combinations of three kinds of protein descriptors, two kinds of ligand descriptors and multiplication cross-terms were constructed in our study. Results The results show that structure similarity descriptors are better than sequence similarity descriptors and geometry descriptors in the leftacterization of HDACs. Furthermore, the predictive ability was not improved by introducing the cross-terms in our models. Finally, a best PCM model based on protein structure similarity descriptors and 32-dimensional general descriptors was derived (R2 = 0.9897, Qtest2 = 0.7542), which shows a powerful ability to screen selective HDAC inhibitors. Conclusions Our best model not only predict the activities of inhibitors for each HDAC isoform, but also screen and distinguish class-selective inhibitors and even more isoform-selective inhibitors, thus it provides a potential way to discover or design novel candidate antitumor drugs with reduced side effect. PMID:22913517

2012-01-01

81

Histone Acetylation Level and Histone Acetyltransferase/Deacetylase Activity in Ejaculated Sperm from Normozoospermic Men  

PubMed Central

Purpose The aim of this work was to evaluate nuclear histone acetylation level and total histone acetyltransferase (HAT) and deacetylase (HDAC) activity in ejaculated sperm and their relevance to conventional sperm parameters. Materials and Methods Thirty-three normozoospermic men were included in this study. Semen samples were processed by swim-up and then immunostained by six acetylation antibodies (H3K9ac, H3K14ac, H4K5ac, H4K8ac, H4K12ac, and H4K16ac). Our preliminary study verified the expression of HAT/HDAC1 in mature human sperm. From vitrified-warmed sperm samples, total HAT/HDAC activity was measured by commercially available kits. Nuclear DNA integrity was also measured by TUNEL assay. Results The levels of six acetylation marks were not related with conventional sperm parameters including sperm DNA fragmentation index (DFI) as well as HAT/HDAC activity. However, sperm DFI was positively correlated with HAT activity (r=0.038 after adjustment, p<0.02). HAT activity showed a negative relationship with HDAC activity (r=-0.51, p<0.01). Strict morphology was negatively correlated with acetylation enzyme index (=HAT activity/HDAC activity) (r=-0.53, p<0.01). Conclusion Our works demonstrated a significant relationship of acetylation-associated enzyme activity and strict morphology or sperm DFI. PMID:25048493

Kim, Jee Hyun; Lee, Jang Mi; Suh, Chang Suk; Kim, Seok Hyun

2014-01-01

82

Evaluation of Histone Deacetylases as Drug Targets in Huntington’s Disease models  

PubMed Central

The family of histone deacetylases (HDACs) has recently emerged as important drug targets for treatment of slow progressive neurodegenerative disorders, including Huntington’s disease (HD). Broad pharmaceutical inhibition of HDACs has shown neuroprotective effects in various HD models. Here we examined the susceptibility of HDAC targets for drug treatment in affected brain areas during HD progression. We observed increased HDAC1 and decreased HDAC4, 5 and 6 levels, correlating with disease progression, in cortices and striata of HD R6/2 mice. However, there were no significant changes in HDAC protein levels, assessed in an age-dependent manner, in HD knock-in CAG140 mice and we did not observe significant changes in HDAC1 levels in human HD brains. We further assessed acetylation levels of ?-tubulin, as a biomarker of HDAC6 activity, and found it unchanged in cortices from R6/2, knock-in, and human subjects at all disease stages. Inhibition of deacetylase activities was identical in cortical extracts from R6/2 and wild-type mice treated with a class II-selective HDAC inhibitor. Lastly, treatment with class I- and II-selective HDAC inhibitors showed similar responses in HD and wild-type rat striatal cells. In conclusion, our results show that class I and class II HDAC targets are present and accessible for chronic drug treatment during HD progression and provide impetus for therapeutic development of brain-permeable class- or isoform-selective inhibitors. PMID:20877454

Quinti, Luisa; Chopra, Vanita; Rotili, Dante; Valente, Sergio; Amore, Allison; Franci, Gianluigi; Meade, Sarah; Valenza, Marta; Altucci, Lucia; Maxwell, Michele M.; Cattaneo, Elena; Hersch, Steven; Mai, Antonello; Kazantsev, Aleksey

2010-01-01

83

Histone Deacetylase Inhibitors: A Chemical Genetics Approach to Understanding Cellular Functions  

PubMed Central

There are eleven zinc dependent histone deacetylases (HDAC) in humans which have histones and many non-histone substrates. The substrates of these enzymes include proteins that have a role in regulation of gene expression, cell proliferation, cell migration, cell death, immune pathways and angiogenesis. Inhibitors of HDACs (HDACi) have been developed which alter the structure and function of these proteins, causing molecular and cellular changes that induce transformed cell death. The HDACi are being developed as anti-cancer drugs and have therapeutic potential for many non-oncologic diseases. PMID:20594930

Marks, Paul A.

2014-01-01

84

Microarray Deacetylation Maps Determine Genome-Wide Functions for Yeast Histone Deacetylases  

Microsoft Academic Search

Yeast contains a family of five related histone deacetylases (HDACs) whose functions are known at few genes. Therefore, we used chromatin immunoprecipitation and intergenic microarrays to generate genome-wide HDAC enzyme activity maps. Rpd3 and Hda1 deacetylate mainly distinct promoters and gene classes where they are recruited largely by novel mechanisms. Hda1 also deacetylates subtelomeric domains containing normally repressed genes that

Daniel Robyr; Yuko Suka; Ioannis Xenarios; Siavash K. Kurdistani; Amy Wang; Noriyuki Suka; Michael Grunstein

2002-01-01

85

Histone Deacetylase Enzymes as Potential Drug Targets in Cancer and Parasitic Diseases  

PubMed Central

The elucidation of the mechanisms of transcriptional activation and repression in eukaryotic cells has shed light on the important role of acetylation-deacetylation of histones mediated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. Another group belonging to the large family of sirtuins (silent information regulators (SIRs)) has an (nicotinamide adenine dinucleotide) NAD+-dependent HDAC activity. Several inhibitors of HDACs (HDIs) have been shown to exert antitumor effects. Interestingly, some of the HDIs exerted a broad spectrum of antiprotozoal activity. The purpose of this review is to analyze some of the current data related to the deacetylase enzymes as a possible target for drug development in cancer and parasitic diseases with special reference to protozoan infections. Given the structural differences among members of this family of enzymes, development of specific inhibitors will not only allow selective therapeutic intervention, but may also provide a powerful tool for functional study of these enzymes. PMID:16883049

Ouaissi, Mehdi; Ouaissi, Ali

2006-01-01

86

Targeting Histone Deacetylases for Cancer Therapy: From Molecular Mechanisms to Clinical Implications  

PubMed Central

Genetic abnormalities have been conventionally considered as hallmarks of cancer. However, studies over the past decades have demonstrated that epigenetic regulation also participates in the development of cancer. The fundamental patterns of epigenetic components, such as DNA methylation and histone modifications, are frequently altered in tumor cells. Acetylation is one of the best characterized modifications of histones, which is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDACs are a group of enzymes which catalyze the removal of the acetyl groups of both histones and non-histone proteins. HDACs are involved in modulating most key cellular processes, including transcriptional regulation, apoptosis, DNA damage repair, cell cycle control, autophagy, metabolism, senescence and chaperone function. Because HDACs have been found to function incorrectly in cancer, various HDAC inhibitors are being investigated to act as cancer chemotherapeutics. The primary purpose of this paper is to summarize recent studies of the links between HDACs and cancer, and further discuss the underlying mechanisms of anti-tumor activities of HDAC inhibitors and clinical implications. PMID:25013383

Li, Zhiming; Zhu, Wei-Guo

2014-01-01

87

Prefrontal Cortical Dysfunction After Overexpression of Histone Deacetylase 1  

PubMed Central

Background Postmortem brain studies have shown that HDAC1—a lysine deacetylase with broad activity against histones and nonhistone proteins—is frequently expressed at increased levels in prefrontal cortex (PFC) of subjects diagnosed with schizophrenia and related disease. However, it remains unclear whether upregulated expression of Hdac1 in the PFC could affect cognition and behavior. Methods Using adeno-associated virus, an Hdac1 transgene was expressed in young adult mouse PFC, followed by behavioral assays for working and long-term memory, repetitive activity, and response to novelty. Prefrontal cortex transcriptomes were profiled by microarray. Antipsychotic drug effects were explored in mice treated for 21 days with haloperidol or clozapine. Results Hdac1 overexpression in PFC neurons and astrocytes resulted in robust impairments in working memory, increased repetitive behaviors, and abnormal locomotor response profiles in novel environments. Long-term memory remained intact. Over 300 transcripts showed subtle but significant changes in Hdac1-overexpressing PFC. Major histocompatibility complex class II (MHC II)-related transcripts, including HLA-DQA1/H2-Aa, HLA-DQB1/H2-Ab1, and HLA-DRB1/H2-Eb1, located in the chromosome 6p21.3-22.1 schizophrenia and bipolar disorder risk locus, were among the subset of genes with a more robust (>1.5-fold) downregulation in expression. Hdac1 levels declined during the course of normal PFC development. Antipsychotic drug treatment, including the atypical clozapine, did not affect Hdac1 levels in PFC but induced expression of multiple MHC II transcripts. Conclusions Excessive HDAC1 activity, due to developmental defects or other factors, is associated with behavioral alterations and dysregulated expression of MHC II and other gene transcripts in the PFC. PMID:23664640

Jakovcevski, Mira; Bharadwaj, Rahul; Straubhaar, Juerg; Gao, Guangping; Gavin, David P.; Jakovcevski, Igor; Mitchell, Amanda C.; Akbarian, Schahram

2013-01-01

88

Melatonin prevents neonatal dexamethasone induced programmed hypertension: histone deacetylase inhibition.  

PubMed

Adulthood hypertension can be programmed by corticosteroid exposure in early life. Oxidative stress, epigenetic regulation by histone deacetylases (HDACs), and alterations of renin-angiotensin system (RAS) are involved in the developmental programming of hypertension. We examined whether melatonin prevented neonatal dexamethasone (DEX)-induced programmed hypertension and how melatonin prevented these processes. We also examined whether HDAC inhibition by trichostatin A (TSA, a HDAC inhibitor) had similar effects. Male offspring were assigned to 5 groups (n=6/group): control, DEX, melatonin, DEX+melatonin, and DEX+TSA. Male rat pups were injected i.p. with DEX on day 1 (0.5mg/kg BW), day 2 (0.3mg/kg BW), and day 3 (0.1mg/kg BW) after birth. Melatonin was administered in drinking water at the dose of 0.01% during the lactation period. The DEX+TSA group received DEX and 0.5mg/kg TSA subcutaneous injection once daily for 1 week. All rats were killed at 16 weeks of age. Neonatal DEX exposure induced hypertension in male offspring at 16 weeks of age, which melatonin prevented. Neonatal DEX exposure decreased gene expression related to apoptosis, nephrogenesis, RAS, and sodium transporters. Yet DEX treatment increased protein levels of HDAC-1, -2, and -3 in the kidney. Melatonin therapy preserved the decreases of gene expression and decreased HDACs. Similarly, HDAC inhibition prevented DEX-induced programmed hypertension. In conclusion, melatonin therapy exerts a long-term protection against neonatal DEX-induced programmed hypertension. Its beneficial effects include alterations of RAS components and inhibition of class I HDACs. Given that the similar protective effects of melatonin and TSA, melatonin might inhibit HDACs to epigenetic regulation of hypertension-related genes to prevent programmed hypertension. PMID:25090636

Wu, Ting-Hsin; Kuo, Hsuan-Chang; Lin, I-Chun; Chien, Shao-Ju; Huang, Li-Tung; Tain, You-Lin

2014-10-01

89

The role of histone deacetylase 2 and its posttranslational modifications in cardiac hypertrophy.  

PubMed

Cardiac hypertrophy is a form of global remodeling, though its initial step seems to be an adaptation to the increased hemodynamic demands. The characteristics of cardiac hypertrophy include the functional reactivation of arrested fetal gene program, where histone deacetylases (HDACs) are closely linked in the development of the process. To date, mammalian HDACs are divided into four classes of I, II, III, and IV. By structural similarities, class II HDACs are then subdivided into IIa and IIb. Among HDACs, HDAC2, 4, 5, and 9 are reported to be involved in hypertrophic response; HDAC4, 5, and 9 are negative regulator, whereas HDAC2 is a pro-hypertrophic mediator. The molecular function and regulation of class IIa HDACs largely depend on the phosphorylation-mediated cytosolic redistribution, whereas those of HDAC2 take place mainly in the nucleus. In response to stresses, posttranslational modification (PTM) processes, dynamic modifications after translation of proteins, are involved in the regulation of the activities of those hypertrophy-related HDACs. In this article, we briefly review 1) the activation of HDAC2 in the development of cardiac hypertrophy and 2) the PTM of HDAC2 and its implications in the regulation of HDAC2 activity. PMID:25388210

Eom, Gwang Hyeon; Kook, Hyun

2014-11-12

90

Histone deacetylase 3 is necessary for proper brain development.  

PubMed

The functional role of histone deacetylase 3 (HDAC3) in the developing brain has yet to be elucidated. We show that mice lacking HDAC3 in neurons and glia of the central nervous system, Nes-Cre/HDAC3 conditional KO mice, show major abnormalities in the cytoarchitecture of the neocortex and cerebellum and die within 24 h of birth. Later-born neurons do not localize properly in the cortex. A similar mislocalization is observed with cerebellar Purkinje neurons. Although the proportion of astrocytes is higher than normal, the numbers of oligodendrocytes are reduced. In contrast, conditional knockout of HDAC3 in neurons of the forebrain and certain other brain regions, using Thy1-Cre and calcium/calmodulin dependent protein kinase II ?-Cre for ablation, produces no overt abnormalities in the organization of cells within the cortex or of cerebellar Purkinje neurons at birth. However, both lines of conditional knockout mice suffer from progressive hind limb paralysis and ataxia and die around 6 weeks after birth. The mice display an increase in overall numbers of cells, higher numbers of astrocytes, and Purkinje neuron degeneration. Taken together, our results demonstrate that HDAC3 plays an essential role in regulating brain development, with effects on both neurons and glia in different brain regions. PMID:25339172

Norwood, Jordan; Franklin, Jade M; Sharma, Dharmendra; D'Mello, Santosh R

2014-12-12

91

Effect of Histone Deacetylase Inhibitor JNJ-26481585 in Pain.  

PubMed

Recent studies have shown that histone deacetylase (HDAC) inhibitors can alleviate inflammatory and neuropathic pain. We investigated the effects of JNJ-26481585, a pan-HDAC inhibitor on basal mechanical sensitivity. Unlike previous reports for HDAC inhibitors, JNJ-26481585 induced mechanical hypersensitivity in mice. This effect was reversible with gabapentin. Voltage-dependent calcium channel subunit alpha-2/delta-1, one of the putative targets for gabapentin, was upregulated in the spinal cord from JNJ-26481585-treated mice. Transcriptional profiling of spinal cord from JNJ-26481585-treated mice showed significant alterations in pathways involved in axon guidance, suggesting overlap in mechanisms underlying neurotoxicity caused by other known chemotherapeutic agents. To investigate the mechanisms underlying the development of pain, RAW 264.7 mouse macrophage cells were treated with JNJ-26481585. There was a dose- and time-dependent activation of nuclear factor-kappaB and interleukin-1? increase. Thus, alterations in the axon guidance pathway, increase in voltage-dependent calcium channel alpha(2)delta-1 subunit, and the induction of proinflammatory mediators by JNJ-26481585 could all contribute to increased mechanical sensitivity. Our data indicate that the effect of HDAC inhibitors may be unique to the compound studied and highlights the potential to develop chemotherapy-induced peripheral neuropathy with the use of a pan-HDAC inhibitor for cancer treatment, and this pain may be alleviated by gabapentin. PMID:25085711

Capasso, Kathryn E; Manners, Melissa T; Quershi, Rehman A; Tian, Yuzhen; Gao, Ruby; Hu, Huijuan; Barrett, James E; Sacan, Ahmet; Ajit, Seena K

2014-08-01

92

Histone Deacetylase 7 Promotes PML Sumoylation and Is Essential for PML Nuclear Body Formation  

Microsoft Academic Search

Promyelocytic leukemia protein (PML) sumoylation has been proposed to control the formation of PML nuclear bodies (NBs) and is crucial for PML-dependent cellular processes, including apoptosis and transcrip- tional regulation. However, the regulatory mechanisms of PML sumoylation and its specific roles in the formation of PML NBs remain largely unknown. Here, we show that histone deacetylase 7 (HDAC7) knock- down

Chengzhuo Gao; Chun-Chen Ho; Erin Reineke; Minh Lam; Xiwen Cheng; Kristopher J. Stanya; Yu Liu; Sharmistha Chakraborty; Hsiu-Ming Shih; Hung-Ying Kao

2008-01-01

93

Histone deacetylases and their role in motor neuron degeneration  

PubMed Central

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, characterized by the progressive loss of motor neurons. The cause of this selective neuronal death is unknown, but transcriptional dysregulation is recently emerging as an important factor. The physical substrate for the regulation of the transcriptional process is chromatin, a complex assembly of histones and DNA. Histones are subject to several post-translational modifications, like acetylation, that are a component of the transcriptional regulation process. Histone acetylation and deacetylation is performed by a group of enzymes (histone acetyltransferases (HATs) and deacetylases, respectively) whose modulation can alter the transcriptional state of many regions of the genome, and thus may be an important target in diseases that share this pathogenic process, as is the case for ALS. This review will discuss the present evidence of transcriptional dysregulation in ALS, the role of histone deacetylases (HDACs) in disease pathogenesis, and the novel pharmacologic strategies that are being comprehensively studied to prevent motor neuron death, with focus on sirtuins (SIRT) and their effectors. PMID:24367290

Lazo-Gómez, Rafael; Ramírez-Jarquín, Uri N.; Tovar-y-Romo, Luis B.; Tapia, Ricardo

2013-01-01

94

Discovery and activity profiling of thailandepsins A through F, potent histone deacetylase inhibitors, from Burkholderia thailandensis E264†‡  

PubMed Central

Three new bicyclic depsipeptides, which are related to the previously reported thailandepsins A (1), B (2) and C (3), were discovered from the culture broth of Burkholderia thailandensis E264 when supplemented with amino acid precursors, and were subsequently named as thailandepsins D (4), E (5) and F (6), respectively. Enzyme assays showed that 1–6 are potent histone deacetylase (HDAC) inhibitors, particularly toward HDAC1 which represents class I human HDACs. PMID:23997923

Wang, Cheng; Flemming, Creston J.

2013-01-01

95

Histone Deacetylase 1 and 3 Regulate the Mesodermal Lineage Commitment of Mouse Embryonic Stem Cells  

PubMed Central

The important role of histone acetylation alteration has become increasingly recognized in mesodermal lineage differentiation and development. However, the contribution of individual histone deacetylases (HDACs) to mesoderm specification remains poorly understood. In this report, we found that trichostatin A (TSA), an inhibitor of histone deacetylase (HDACi), could induce early differentiation of embryonic stem cells (ESCs) and promote mesodermal lineage differentiation. Further analysis showed that the expression levels of HDAC1 and 3 are decreased gradually during ESCs differentiation. Ectopic expression of HDAC1 or 3 significantly inhibited differentiation into the mesodermal lineage. By contrast, loss of either HDAC1 or 3 enhanced the mesodermal differentiation of ESCs. Additionally, we demonstrated that the activity of HDAC1 and 3 is indeed required for the regulation of mesoderm gene expression. Furthermore, HDAC1 and 3 were found to interact physically with the T-box transcription factor T/Bry, which is critical for mesodermal lineage commitment. These findings indicate a key mechanism for the specific role of HDAC1 and 3 in mammalian mesoderm specification. PMID:25412078

Lv, Weiying; Guo, Xudong; Wang, Guiying; Xu, Yanxin; Kang, Jiuhong

2014-01-01

96

3-Hydroxypyridin-2-thione as Novel Zinc Binding Group for Selective Histone Deacetylase Inhibition  

PubMed Central

Small molecules bearing hydroxamic acid as the zinc binding group (ZBG) have been the most effective histone deacetylase inhibitor (HDACi) to date. However, concerns about the pharmacokinetic liabilities of the hydroxamic acid moiety have stimulated research efforts aimed at finding alternative non-hydroxamate ZBGs. We have identified 3-hydroxypyridin-2-thione (3-HPT) as a novel ZBG that is compatible with HDAC inhibition. 3-HPT inhibits HDAC 6 and HDAC 8 with an IC50 of 681 nM and 3675 nM respectively. Remarkably, 3-HPT gives no inhibition of HDAC 1. Subsequent optimization led to several novel 3HPT-based HDACi that are selective for HDAC 6 and HDAC 8. Furthermore, a subset of these inhibitors induces apoptosis in various cancer cell lines. PMID:23547652

Patil, Vishal; Sodji, Quaovi H.; Kornacki, James R.; Mrksich, Milan; Oyelere, Adegboyega K.

2013-01-01

97

The clinical development of histone deacetylase inhibitors as targeted anticancer drugs  

PubMed Central

Importance of the field Histone deacetylase (HDAC) inhibitors are being developed as a new, targeted class of anticancer drugs. Area covered in this review This review focuses on the mechanisms of action of the HDAC inhibitors, which selectively induce cancer cell death. What the reader will gain There are 11 zinc-dependent HDACs in humans and the biological roles of these lysine deacetylases are not completely understood. It is clear that these different HDACs are not redundant in their activity. This review focuses on the mechanisms by which HDAC inhibitors can induce transformed cell growth arrest and cell death, inhibit cell mobility and have antiangiogenesis activity. There are more than a dozen HDAC inhibitors, including hydroxamates, cyclic peptides, benzamides and fatty acids, in various stages of clinical trials and many more compounds in preclinical development. The chemically different HDAC inhibitors may target different HDACs. Take home message There are extensive preclinical studies with transformed cells in culture and tumor-bearing animal models, as well as limited clinical studies reported to date, which indicate that HDAC inhibitors will be most useful when used in combination with cytotoxic or other targeted anticancer agents. PMID:20687783

Marks, Paul A

2014-01-01

98

Histone Deacetylase Inhibitors Sensitize Prostate Cancer Cells to Agents that Produce DNA Double-Strand Breaks by Targeting Ku70Acetylation  

Microsoft Academic Search

This study reports a histone deacetylation-independent mechanism whereby histone deacetylase (HDAC) inhibitors sensitize prostate cancer cells to DNA-damaging agents by targeting Ku70acetylation. Ku70represents a crucial compo- nent of the nonhomologous end joining repair machinery for DNA double-strand breaks (DSB). Our data indicate that pretreatment of prostate cancer cells with HDAC inhibitors (trichostatin A, suberoylanilide hydroxamic acid, MS-275, and OSU-HDAC42) led

Chang-Shi Chen; Yu-Chieh Wang; Hsiao-Ching Yang; Po-Hsien Huang; Samuel K. Kulp; Chih-Cheng Yang; Yen-Shen Lu; Shigemi Matsuyama; Ching-Yu Chen; Ching-Shih Chen

2007-01-01

99

R306465 is a novel potent inhibitor of class I histone deacetylases with broad-spectrum antitumoral activity against solid and haematological malignancies  

Microsoft Academic Search

R306465 is a novel hydroxamate-based histone deacetylase (HDAC) inhibitor with broad-spectrum antitumour activity against solid and haematological malignancies in preclinical models. R306465 was found to be a potent inhibitor of HDAC1 and -8 (class I) in vitro. It rapidly induced histone 3 (H3) acetylation and strongly upregulated expression of p21waf1,cip1, a downstream component of HDAC1 signalling, in A2780 ovarian carcinoma

J Arts; P Angibaud; A Mariën; W Floren; B Janssens; P King; J van Dun; L Janssen; T Geerts; R W Tuman; D L Johnson; L Andries; M Jung; M Janicot; K van Emelen

2007-01-01

100

Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila.  

PubMed

Proteins with expanded polyglutamine repeats cause Huntington's disease and other neurodegenerative diseases. Transcriptional dysregulation and loss of function of transcriptional co-activator proteins have been implicated in the pathogenesis of these diseases. Huntington's disease is caused by expansion of a repeated sequence of the amino acid glutamine in the abnormal protein huntingtin (Htt). Here we show that the polyglutamine-containing domain of Htt, Htt exon 1 protein (Httex1p), directly binds the acetyltransferase domains of two distinct proteins: CREB-binding protein (CBP) and p300/CBP-associated factor (P/CAF). In cell-free assays, Httex1p also inhibits the acetyltransferase activity of at least three enzymes: p300, P/CAF and CBP. Expression of Httex1p in cultured cells reduces the level of the acetylated histones H3 and H4, and this reduction can be reversed by administering inhibitors of histone deacetylase (HDAC). In vivo, HDAC inhibitors arrest ongoing progressive neuronal degeneration induced by polyglutamine repeat expansion, and they reduce lethality in two Drosophila models of polyglutamine disease. These findings raise the possibility that therapy with HDAC inhibitors may slow or prevent the progressive neurodegeneration seen in Huntington's disease and other polyglutamine-repeat diseases, even after the onset of symptoms. PMID:11607033

Steffan, J S; Bodai, L; Pallos, J; Poelman, M; McCampbell, A; Apostol, B L; Kazantsev, A; Schmidt, E; Zhu, Y Z; Greenwald, M; Kurokawa, R; Housman, D E; Jackson, G R; Marsh, J L; Thompson, L M

2001-10-18

101

Isoform-specific histone deacetylase inhibitors: the next step?  

PubMed

Histone deacetylases (HDACs) have emerged as attractive drug targets, particularly for neoplastic indications. This large family is divided into four classes, of which three consist of zinc-dependent enzymes, and inhibitors of these are the subject of this review. Currently, there are several inhibitors advancing through clinical trials, all of which inhibit multiple isoforms of these three classes. While promising, these compounds have exhibited toxicities in the clinic that might limit their potential, particularly in solid tumors. It may be possible to reduce some of the toxicity by specifically targeting only the isoform(s) involved in maintaining that particular tumor and spare other isoforms that are uninvolved or even beneficial. This review examines the selectivity and toxicity of HDAC inhibitors currently in clinic, comparing pan-HDAC inhibitors to Class I selective compounds. The rationale for isoform-specific inhibitors is examined. The current status of isoform-specific inhibitor development is analyzed, especially inhibitors of HDAC1, 2, 4 and 8 enzymes, and the potential clinical utility of these compounds is discussed. PMID:19289255

Balasubramanian, Sriram; Verner, Erik; Buggy, Joseph J

2009-08-01

102

Thailandepsins: Bacterial Products with Potent Histone Deacetylase Inhibitory Activities and Broad-Spectrum Antiproliferative Activities  

PubMed Central

Histone deacetylase (HDAC) inhibitors have emerged as a new class of anticancer drugs, with one synthetic compound, SAHA (vorinostat, Zolinza®; 1), and one natural product, FK228 (depsipeptide, romidepsin, Istodax®; 2), approved by FDA for clinical use. Our studies of FK228 biosynthesis in Chromobacterium violaceum No. 968 led to the identification of a cryptic biosynthetic gene cluster in the genome of Burkholderia thailandensis E264. Genome mining and genetic manipulation of this gene cluster further led to the discovery of two new products, thailandepsin A (6) and thailandepsin B (7). HDAC inhibition assays showed that thailandepsins have selective inhibition profiles different from that of FK228, with comparable inhibitory activities to those of FK228 toward human HDAC1, HDAC2, HDAC3, HDAC6, HDAC7 and HDAC9, but weaker inhibitory activities than FK228 toward HDAC4 and HDAC8, the later of which could be beneficial. NCI-60 anticancer screening assays showed that thailandepsins possess broad-spectrum antiproliferative activities with GI50 for over 90% of the tested cell lines at low nanomolar concentrations, and potent cytotoxic activities towards certain types of cell lines, particularly for those derived from colon, melanoma, ovarian and renal cancers. Thailandepsins thus represent new naturally produced HDAC inhibitors that are promising for anticancer drug development. PMID:21793558

Wang, Cheng; Henkes, Leonhard M.; Doughty, Leah B.; He, Min; Wang, Difei; Meyer-Almes, Franz-Josef; Cheng, Yi-Qiang

2011-01-01

103

Aberrant HDAC2-Mediated Histone Modifications and Synaptic Plasticity in the Amygdala Predisposes to Anxiety and Alcoholism  

PubMed Central

Background Epigenetic mechanisms have been implicated in psychiatric disorders, including alcohol dependence. However, the epigenetic basis and role of specific histone deacetylase (HDAC) isoforms in the genetic predisposition to anxiety and alcoholism is unknown. Methods We measured amygdaloid HDAC activity, levels of HDAC isoforms and histone H3 acetylation in selectively-bred alcohol-preferring (P) and -nonpreferring (NP) rats. We employed HDAC2 siRNA infusion into the central nucleus of amygdala (CeA) of P rats to determine the causal role of HDAC2 in anxiety-like and alcohol-drinking behaviors. Chromatin immunoprecipitation analysis was performed to examine the histone acetylation status of brain-derived neurotrophic factor (BDNF) and activity-regulated cytoskeleton associated protein (Arc) genes. Golgi-Cox staining was performed to measure dendritic spine density. Results We found that P rats innately display higher nuclear HDAC activity and HDAC2, but not HDAC 1, 3, 4, 5, and 6 protein levels, and lower acetylation of H3-K9, but not H3-K14, in the CeA and medial nucleus of amygdala (MeA) compared with NP rats. Acute ethanol exposure decreased amygdaloid HDAC activity and HDAC2 protein levels, increased global and gene (BDNF and Arc)-specific histone acetylation and attenuated anxiety-like behaviors in P rats, but had no effects in NP rats. HDAC2 knockdown in the CeA attenuated anxiety-like behaviors and voluntary alcohol, but not sucrose, consumption in P rats and increased histone acetylation of BDNF and Arc with a resultant increase in protein levels that correlated with increased dendritic spine density. Conclusions These novel data demonstrate the role of HDAC2-mediated epigenetic mechanisms in anxiety and alcoholism. PMID:23485013

Moonat, Sachin; Sakharkar, Amul J.; Zhang, Huaibo; Tang, Lei; Pandey, Subhash C.

2013-01-01

104

A new role for histone deacetylase 5 in the maintenance of long telomeres.  

PubMed

Telomeres are major regulators of genome stability and cell proliferation. A detailed understanding of the mechanisms involved in their maintenance is of foremost importance. Of those, telomere chromatin remodeling is probably the least studied; thus, we intended to explore the role of a specific histone deacetylase on telomere maintenance. We uncovered a new role for histone deacetylase 5 (HDAC5) in telomere biology. We report that HDAC5 is recruited to the long telomeres of osteosarcoma- and fibrosarcoma-derived cell lines, where it ensures proper maintenance of these repetitive regions. Indeed, depletion of HDAC5 by RNAi resulted in the shortening of longer telomeres and homogenization of telomere length in cells that use either telomerase or an alternative mechanism of telomere maintenance. Furthermore, we present evidence for the activation of telomere recombination on depletion of HDAC5 in fibrosarcoma telomerase-positive cancer cells. Of potential importance, we also found that depletion of HDAC5 sensitizes cancer cells with long telomeres to chemotherapeutic drugs. Cells with shorter telomeres were used to control the specificity of HDAC5 role in the maintenance of long telomeres. HDAC5 is essential for the length maintenance of long telomeres and its depletion is required for sensitization of cancer cells with long telomeres to chemotherapy. PMID:23729589

Novo, Clara Lopes; Polese, Catherine; Matheus, Nicolas; Decottignies, Anabelle; Londono-Vallejo, Arturo; Castronovo, Vincent; Mottet, Denis

2013-09-01

105

Activation and inhibition of histone deacetylase 8 by monovalent cations.  

PubMed

The metal-dependent histone deacetylases (HDACs) catalyze hydrolysis of acetyl groups from acetyllysine side chains and are targets of cancer therapeutics. Two bound monovalent cations (MVCs) of unknown function have been previously observed in crystal structures of HDAC8; site 1 is near the active site, whereas site 2 is located > 20 A from the catalytic metal ion. Here we demonstrate that one bound MVC activates catalytic activity (K(1/2) = 3.4 mM for K(+)), whereas the second, weaker-binding MVC (K(1/2) = 26 mM for K(+)) decreases catalytic activity by 11-fold. The weaker binding MVC also enhances the affinity of the HDAC inhibitor suberoylanilide hydroxamic acid by 5-fold. The site 1 MVC is coordinated by the side chain of Asp-176 that also forms a hydrogen bond with His-142, one of two histidines important for catalytic activity. The D176A and H142A mutants each increase the K(1/2) for potassium inhibition by > or = 40-fold, demonstrating that the inhibitory cation binds to site 1. Furthermore, the MVC inhibition is mediated by His-142, suggesting that this residue is protonated for maximal HDAC8 activity. Therefore, His-142 functions either as an electrostatic catalyst or a general acid. The activating MVC binds in the distal site and causes a time-dependent increase in activity, suggesting that the site 2 MVC stabilizes an active conformation of the enzyme. Sodium binds more weakly to both sites and activates HDAC8 to a lesser extent than potassium. Therefore, it is likely that potassium is the predominant MVC bound to HDAC8 in vivo. PMID:20029090

Gantt, Stephanie L; Joseph, Caleb G; Fierke, Carol A

2010-02-26

106

Class I histone deacetylase activity is required for proliferation of renal epithelial cells  

PubMed Central

The process of renal regeneration after acute kidney injury is thought to recapitulate renal development, and proliferation of renal proximal tubular cells (RPTCs) is a critical step in the regenerative response. Recent studies indicate that class I histone deacetylases (HDACs) are required for embryonic kidney gene expression, growth, and differentiation. The role and underlying mechanisms of class I HDAC activation in RPTC proliferation, however, remain unclear. In this study, we used cultured RPTCs to examine this issue since four class I HDAC isoforms (1, 2, 3, and 8) are abundantly expressed in this cell type. Blocking class I HDAC activity with a highly selective inhibitor, MS-275, induced global histone H3 hyperacetylation, reduced RPTC proliferation, and diminished expression of cyclin D1 and proliferating cell nuclear antigen. Silencing HDAC1, 3, or 8 with small interfering RNA resulted in similar biological effects. Activation of epidermal growth factor receptor (EGFR) and signal transducers and activators of transcription 3 (STAT3) was required for RPTC proliferation, and STAT3 functioned downstream of EGFR. Treatment with MS-275 or knockdown of HDAC1, 3, or 8 suppressed EGFR expression and phosphorylation, and silencing HDAC1 and 3 also reduced STAT3 phosphorylation. However, HDAC2 downregulation did not affect RPTC proliferation and phosphorylation of EGFR and STAT3. Collectively, these data reveal a critical role of class I HDACs in mediating proliferation of renal epithelial cells through activation of the EGFR/STAT3 signaling pathway. PMID:23698124

Tang, Jinhua; Yan, Yanli; Zhao, Ting C.; Bayliss, George; Yan, Haidong

2013-01-01

107

MS275, a novel histone deacetylase inhibitor with selectivity against HDAC1, induces degradation of FLT3 via inhibition of chaperone function of heat shock protein 90 in AML cells  

Microsoft Academic Search

This study explored the effect of MS-275, a novel histone deacetylase inhibitor (HDACI), against a variety of human leukemia cells with defined genetic alterations. MS-275 profoundly induced growth arrest of acute myelogenous leukemia (AML) MOLM13 and biphenotypic leukemia MV4-11 cells, which possess internal tandem duplication mutation in the fms-like tyrosine kinase 3 (FLT3) gene (FLT3-ITD), with IC50s less than 1?M,

Chie Nishioka; Takayuki Ikezoe; Jing Yang; Seisho Takeuchi; H. Phillip Koeffler; Akihito Yokoyama

2008-01-01

108

Histone deacetylase inhibitors: molecular mechanisms of action and clinical trials as anti-cancer drugs  

PubMed Central

Histone deacetylase (HDAC) inhibitors are a relatively new class of anti-cancer agents that play important roles in epigenetic or non-epigenetic regulation, inducing death, apoptosis, and cell cycle arrest in cancer cells. Recently, their use has been clinically validated in cancer patients resulting in the approval of two HDAC inhibitors, vorinostat and depsipetide, by the FDA. Also, clinical trials of several HDAC inhibitors for use as anti-cancer drugs (alone or in combination with other anti-cancer therapeutics) are ongoing. However, the molecular mechanisms underlying the response to HDAC inhibitors in cancer patients are not fully understood. In this review, we summarize our understanding of the molecular and biological events that underpin the anticancer effects of HDAC inhibitors and the outcomes of recent clinical trials involving these drugs. PMID:21416059

Kim, Hyun-Jung; Bae, Suk-Chul

2011-01-01

109

Comprehensive analysis for histone acetylation of human colon cancer cells treated with a novel HDAC inhibitor.  

PubMed

Extensive evidence suggests that dysregulation of histone lysine acetylation is intimately linked with the development of cancer in epigenetic level. Histone acetylation on lysine is regulated mainly by the "pencil"--Histone acetyltransferases (HATs) and the "eraser"--Histone deacetylases HDACs. Dramatic elevation of global histone deacetylation is considered as a biomarker for cancer. Therefore, current antitumor drug design often targets HDACs, inhibiting overexpressed HDAC in tumor cells with natural or synthesized small molecules like largazole. Recently, a novel largazole derivative (largazole-7) was designed and prepared by replacement of Val 1 with tyrosine, and this modification increases selectivity toward human cancer cells over normal cells more than 100-fold. However, it is unclear about the dynamic level of histone acetylation under the treatment of this drug. It is also unclear whether the other modifications are also affected by largazole-7 treatment. Therefore, a global mapping of modifications on the histone proteins of cancer cell line treated by this drug may be of great benefit to elucidating its molecular mechanisms and exploring its potent as an antitumor drug. To realize the goal, we combined stable isotope labeling by amino acids in cell culture (SILAC) and high resolution MS for comprehensive identification and quantitative analysis of histone lysine acetylation and other modifications of Human Colon Cancer Cells (HCT-116) with and without treatment of largazole-7. In this analysis, we identified 68 histone PTMs in 38 sites on core histones, including lysine acetylation, methylation and butyrylation, a novel lysine modification. Further quantitative analysis not only discovered the global increased acetylated lysines, but also observed the changes of abundance of lysine methylation and butyrylation under stimulation of the drug. To our knowledge, it is the first report that regulation of largazole-7 against lysine butyrylation. Our study expands the catalog of histone marks in cancer, and provides an approach for understanding the known and new epigenetic marks under treatment of drugs. PMID:23888955

Zhao, Yunlong; Fang, Xiuli; Wang, Ye; Zhang, Junmei; Jiang, Sheng; Liu, Zhe; Ma, Zhenyi; Xu, Liyan; Li, Enmin; Zhang, Kai

2014-01-01

110

Expression of histone acetyltransferase GCN5 and histone deacetylase 1 in the cultured mouse preimplantation embryos.  

PubMed

To investigate the possible mechanisms of the abnormal expression patterns of many genes in the embryos in vitro, the expression of histone acetyltransferase GCN5 and histone deacetylase 1 (HDAC1) were detected in mouse preimplantation embryos. For the in vitro group, the pronucleus embryos were obtained from superovulated mice, and cultured in vitro to get the two-cell, four-cell, eightcell, morula and blastocyst stages embryos. For the in vivo group, embryos at different stages were obtained from pregnant mice directly. Reverse transcription polymerase chain reaction (RT-PCR) and immunocytochemistry were used to detect the mRNA and protein expression levels of GCN5 and HDAC1. Compared with the embryos in vivo, the expression levels of Gcn5 in the embryos in vitro significantly increased except those in four-cell embryos. The expression of Gcn5 in eight-cell embryos in vivo and in four-cell and eight-cell embryos in vitro was higher than those at other stages within the same group. Compared with the expressions of Hdac1 in embryo in vivo, only those at two-cell embryo in vitro showed decreased level. The expression of Hdac1 enhanced after two-cell embryo stage in vitro, but no difference showed in vivo. The protein expression of GCN5and HDAC1 in the embryo in vitro at every stage showed a lower level with the control of those in the embryos in vivo. Our studies indicated that in vitro culture could induce the expressed alteration of GCN5 and HDAC1, which might be related to the expression patterns of many other epigenetically regulated genes. PMID:23888963

Liu, Xiaozhen; Zhao, Dongmei; Zheng, Yingming; Wang, Liya; Qian, Yuli; Xu, Chenming; Huang, Hefeng; Hwa, Yi Lisa; Jin, Fan

2014-01-01

111

Histone deacetylase inhibitors as potential therapeutic approaches for chordoma: an immunohistochemical and functional analysis.  

PubMed

Chordomas are rare malignancies of the axial skeleton. Therapy is mainly restricted to surgery. This study investigates histone deacetylase (HDAC) inhibitors as potential therapeutics for chordomas. Immunohistochemistry (IHC) was performed using the HDAC 1-6 antibodies on 50 chordoma samples (34 primary tumors, 16 recurrences) from 44 patients (27 male, 17 female). Pan-HDAC-inhibitors Vorinostat (SAHA), Panobinostat (LBH-589), and Belinostat (PXD101) were tested for their efficacy in the chordoma cell line MUG-Chor1 via Western blot, cell cycle analysis, caspase 3/7 activity (MUG-Chor1, UCh-1), cleaved caspase-3, and PARP cleavage. p-Values below 0.05 were considered significant. IHC was negative for HDAC1, positive for HDAC2 in most (n = 36; 72%), and for HDACs 3-6 in all specimens available (n = 43; 86%). HDAC6 expression was strongest. SAHA and LBH-589, but not PXD101 caused a significant increase of G2/M phase cells and of cleaved caspase-3 (p = 0.0003, and p = 0.0014 after 72 h, respectively), and a peak of caspase 3/7 activity. PARP cleavage confirmed apoptosis. The presented chordoma series expressed HDACs 2-6 with strongest expression of HDAC6. SAHA and LBH-589 significantly increased apoptosis and changed cell cycle distribution in vitro. HDAC-inhibitors should be further evaluated as therapeutic options for chordoma. PMID:23893747

Scheipl, Susanne; Lohberger, Birgit; Rinner, Beate; Froehlich, Elke Verena; Beham, Alfred; Quehenberger, Franz; Lazáry, Aron; Pal Varga, Peter; Haybaeck, Johannes; Leithner, Andreas; Liegl, Bernadette

2013-12-01

112

Regulated clearance of histone deacetylase 3 protects independent formation of nuclear receptor corepressor complexes.  

PubMed

An important step in transcriptional regulation by corepressors N-CoR and SMRT is the formation of a stable and active histone deacetylase 3 (HDAC3)-containing complex. Although N-CoR and SMRT are thought to bind HDAC3 competitively, multiple studies have shown that they do not interfere with the function of each other. How this functional independence is sustained under the competitive interaction is unclear. Here, we show that the coupling of corepressor expression with HDAC3 degradation allows cells to maintain a stable level of uncomplexed HDAC3, thereby preventing mutual interference in the assembly of N-CoR and SMRT complexes. The free uncomplexed HDAC3 is highly unstable. Unexpectedly, the rate of HDAC3 degradation is inversely correlated with the expression level of corepressors. Our results indicate that reducing one corepressor accelerates HDAC3 clearance, thus preventing an increase in complex formation between HDAC3 and the other corepressor. In addition, this study also indicates that the formation of a stable and active HDAC3-corepressor complex is a stepwise process in which the C terminus of HDAC3 plays a critical role at late steps of the assembly process. PMID:22337871

Guo, Chun; Gow, Chien-Hung; Li, Yali; Gardner, Amanda; Khan, Sohaib; Zhang, Jinsong

2012-04-01

113

Decreased expression of histone deacetylase 10 predicts poor prognosis of gastric cancer patients  

PubMed Central

Aberrant expression of histone deacetylase (HDACs) was associated with carcinogenesis and progression of various tumors. However, the association of HDAC10 with clinical outcomes in gastric cancer patients is unclear. Thus, the objective of the current study was to evaluate the association of expression level of HDAC10 with clinicopathologic factors and prognosis of patients with gastric cancer. The expression level of HDAC10 in 179 paraffin-embedded gastric cancer tissue specimens was examined by immunohistochemistry (IHC). As a result, we found that expression of HDAC10 in gastric cancer was significantly decreased in gastric cancer tissues as compared with adjacent tissues (51.4% vs. 87.3%, P < 0.001). HDAC10 expression was significantly correlated with gender (P = 0.023), tumor size (P = 0.015), histological grade (P = 0.009), tumor invasion (P = 0.033), lymph node metastatic status (P = 0.019) and tumor stage (P = 0.004), but not correlated with age and lauren classification (all P > 0.05). Kaplan-Meier survival curves showed that the overall survival rate was significantly lower in the patients with low expression of HDAC10 compared with those patients with high HDAC10 (P < 0.001). Moreover, multivariate analysis revealed that HDAC10 expression was an independent prognostic factor for gastric cancer patients (P = 0.001). These results suggest that HDAC10 expression could see as a prognosis marker for gastric cancer patients. PMID:25337229

Jin, Ziliang; Jiang, Weihua; Jiao, Feng; Guo, Zhen; Hu, Hai; Wang, Lei; Wang, Liwei

2014-01-01

114

Histone deacetylase-3 interacts with ataxin-7 and is altered in a spinocerebellar ataxia type 7 mouse model.  

PubMed

Spinocerebellar ataxia type 7 (SCA7) is caused by a toxic polyglutamine (polyQ) expansion in the N-terminus of the protein ataxin-7. Ataxin-7 has a known function in the histone acetylase complex, Spt/Ada/Gcn5 acetylase (STAGA) chromatin-remodeling complex. We hypothesized that some histone deacetylase (HDAC) family members would impact the posttranslational modification of normal and expanded ataxin-7 and possibly modulate ataxin-7 function or neurotoxicity associated with the polyQ expansion. Interestingly, when we coexpressed each HDAC family member in the presence of ataxin-7 we found that HDAC3 increased the posttranslational modification of normal and expanded ataxin-7. Specifically, HDAC3 stabilized ataxin-7 and increased modification of the protein. Further, HDAC3 physically interacts with ataxin-7. The physical interaction of HDAC3 with normal and polyQ-expanded ataxin-7 affects the toxicity in a polyQ-dependent manner. We detect robust HDAC3 expression in neurons and glia in the cerebellum and an increase in the levels of HDAC3 in SCA7 mice. Consistent with this we found altered lysine acetylation levels and deacetylase activity in the brains of SCA7 transgenic mice. This study implicates HDAC3 and ataxin-7 interaction as a target for therapeutic intervention in SCA7, adding to a growing list of neurodegenerative diseases that may be treated by HDAC inhibitors. PMID:24160175

Duncan, Carlotta E; An, Mahru C; Papanikolaou, Theodora; Rugani, Caitlin; Vitelli, Cathy; Ellerby, Lisa M

2013-01-01

115

Histone deacetylase inhibition reduces myocardial ischemia-reperfusion injury in mice  

PubMed Central

Limitation of infarct size is a major goal of therapy for acute coronary syndromes, and research has focused on achieving rapid patency of infarct-related vessels. However, new understandings of epigenetic modifications during ischemia suggest additional targeted approaches that have not been extensively explored. Here, we show that ischemia induces histone deacetylase (HDAC) activity in the heart with deacetylation of histones H3/4 in vitro and in vivo. We show, utilizing a standard murine model of ischemia-reperfusion, that chemical HDAC inhibitors significantly reduce infarct area, even when delivered 1 h after the ischemic insult. We demonstrate that HDAC inhibitors prevent ischemia-induced activation of gene programs that include hypoxia inducible factor-1?, cell death, and vascular permeability in vivo and in vitro, thus providing potential mechanisms to explain reduced vascular leak and myocardial injury. In vitro, siRNA knockdown experiments implicate HDAC4 as a mediator of the effects in ischemic cardiac myocytes. These results demonstrate that HDAC inhibitors alter the response to ischemic injury in the heart and reduce infarct size, suggesting novel therapeutic approaches for acute coronary syndromes.—Granger, A., Abdullah, I., Huebner, F., Stout, A., Wang, T., Huebner, T., Epstein, J. A., Gruber, P. J. Histone deacetylase inhibition reduces myocardial ischemia-reperfusion injury in mice. PMID:18606865

Granger, Anne; Abdullah, Ibrahim; Huebner, Faith; Stout, Andrea; Wang, Tao; Huebner, Thomas; Epstein, Jonathan A.; Gruber, Peter J.

2008-01-01

116

3,3'-Diindolylmethane, but not indole-3-carbinol, inhibits histone deacetylase activity in prostate cancer cells.  

PubMed

Increased consumption of cruciferous vegetables is associated with a reduced risk of developing prostate cancer. Indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM) are phytochemicals derived from cruciferous vegetables that have shown promise in inhibiting prostate cancer in experimental models. Histone deacetylase (HDAC) inhibition is an emerging target for cancer prevention and therapy. We sought to examine the effects of I3C and DIM on HDACs in human prostate cancer cell lines: androgen insensitive PC-3 cells and androgen sensitive LNCaP cells. I3C modestly inhibited HDAC activity in LNCaP cells by 25% but no inhibition of HDAC activity was detected in PC-3 cells. In contrast, DIM significantly inhibited HDAC activity in both cell lines by as much as 66%. Decreases in HDAC activity correlated with increased expression of p21, a known target of HDAC inhibitors. DIM treatment caused a significant decrease in the expression of HDAC2 protein in both cancer cell lines but no significant change in the protein levels of HDAC1, HDAC3, HDAC4, HDAC6 or HDAC8 was detected. Taken together, these results show that inhibition of HDAC activity by DIM may contribute to the phytochemicals' anti-proliferative effects in the prostate. The ability of DIM to target aberrant epigenetic patterns, in addition to its effects on detoxification of carcinogens, may make it an effective chemopreventive agent by targeting multiple stages of prostate carcinogenesis. PMID:22800507

Beaver, Laura M; Yu, Tian-Wei; Sokolowski, Elizabeth I; Williams, David E; Dashwood, Roderick H; Ho, Emily

2012-09-15

117

3,3?-Diindolylmethane, but not indole-3-carbinol, inhibits histone deacetylase activity in prostate cancer cells  

SciTech Connect

Increased consumption of cruciferous vegetables is associated with a reduced risk of developing prostate cancer. Indole-3-carbinol (I3C) and 3,3?-diindolylmethane (DIM) are phytochemicals derived from cruciferous vegetables that have shown promise in inhibiting prostate cancer in experimental models. Histone deacetylase (HDAC) inhibition is an emerging target for cancer prevention and therapy. We sought to examine the effects of I3C and DIM on HDACs in human prostate cancer cell lines: androgen insensitive PC-3 cells and androgen sensitive LNCaP cells. I3C modestly inhibited HDAC activity in LNCaP cells by 25% but no inhibition of HDAC activity was detected in PC-3 cells. In contrast, DIM significantly inhibited HDAC activity in both cell lines by as much as 66%. Decreases in HDAC activity correlated with increased expression of p21, a known target of HDAC inhibitors. DIM treatment caused a significant decrease in the expression of HDAC2 protein in both cancer cell lines but no significant change in the protein levels of HDAC1, HDAC3, HDAC4, HDAC6 or HDAC8 was detected. Taken together, these results show that inhibition of HDAC activity by DIM may contribute to the phytochemicals' anti-proliferative effects in the prostate. The ability of DIM to target aberrant epigenetic patterns, in addition to its effects on detoxification of carcinogens, may make it an effective chemopreventive agent by targeting multiple stages of prostate carcinogenesis. -- Highlights: ? DIM inhibits HDAC activity and decreases HDAC2 expression in prostate cancer cells. ? DIM is significantly more effective than I3C at inhibiting HDAC activity. ? I3C has no effect on HDAC protein expression. ? Inhibition of HDAC activity by DIM is associated with increased p21 expression. ? HDAC inhibition may be a novel epigenetic mechanism for cancer prevention with DIM.

Beaver, Laura M., E-mail: beaverl@onid.orst.edu [Linus Pauling Institute, Oregon State University, 307 Linus Pauling Science Center, Corvallis, OR 97331 (United States); School of Biological and Population Health Sciences, Oregon State University, 103 Milam Hall, Corvallis, OR 97331 (United States); Yu, Tian-Wei, E-mail: david.yu@oregonstate.edu [Linus Pauling Institute, Oregon State University, 307 Linus Pauling Science Center, Corvallis, OR 97331 (United States)] [Linus Pauling Institute, Oregon State University, 307 Linus Pauling Science Center, Corvallis, OR 97331 (United States); Sokolowski, Elizabeth I., E-mail: sokolowe@onid.orst.edu [School of Biological and Population Health Sciences, Oregon State University, 103 Milam Hall, Corvallis, OR 97331 (United States); Williams, David E., E-mail: david.williams@oregonstate.edu [Linus Pauling Institute, Oregon State University, 307 Linus Pauling Science Center, Corvallis, OR 97331 (United States); Department of Environmental and Molecular Toxicology, Oregon State University, 1007 Agriculture and Life Sciences Building, Corvallis, OR 97331 (United States); Dashwood, Roderick H., E-mail: rod.dashwood@oregonstate.edu [Linus Pauling Institute, Oregon State University, 307 Linus Pauling Science Center, Corvallis, OR 97331 (United States); Department of Environmental and Molecular Toxicology, Oregon State University, 1007 Agriculture and Life Sciences Building, Corvallis, OR 97331 (United States); Ho, Emily, E-mail: Emily.Ho@oregonstate.edu [Linus Pauling Institute, Oregon State University, 307 Linus Pauling Science Center, Corvallis, OR 97331 (United States) [Linus Pauling Institute, Oregon State University, 307 Linus Pauling Science Center, Corvallis, OR 97331 (United States); School of Biological and Population Health Sciences, Oregon State University, 103 Milam Hall, Corvallis, OR 97331 (United States)

2012-09-15

118

Residues in the 11 Å Channel of Histone Deacetylase 1 Promote Catalytic Activity  

PubMed Central

Histone deacetylase 1 (HDAC1) has been linked to cell growth and cell cycle regulation, which makes it a widely recognized target for anticancer drugs. Whereas variations of the metal-binding and capping groups of HDAC inhibitors have been studied extensively, the role of the linker region is less well known, despite the potency of inhibitors with diverse linkers, such as MS-275. To facilitate a drug design that targets HDAC1, we assessed the influence of residues in the 11 Å channel of the HDAC1 active site on activity by using an alanine scan. The mutation of eight channel residues to alanine resulted in a substantial reduction in deacetylase activity. Molecular dynamics simulations indicated that alanine mutation results in significant movement of the active-site channel, which suggests that channel residues promote HDAC1 activity by influencing substrate interactions. With little characterization of HDAC1 available, the combined experimental and computational results define the active-site residues of HDAC1 that are critical for substrate/inhibitor binding and provide important insight into drug design. PMID:18729444

Weerasinghe, Sujith V. W.; Estiu, Guillermina; Wiest, Olaf; Pflum, Mary Kay H.

2008-01-01

119

Histone deacetylase inhibitors for purging HIV-1 from the latent reservoir.  

PubMed

A reservoir of latently infected memory CD4(+) T cells is believed to be the source of HIV-1 reemergence after discontinuation of antiretroviral therapy. HIV-1 eradication may depend on depletion of this reservoir. Integrated HIV-1 is inaccessible for expression, in part because of histone deacetylases (HDACs). One approach is to exploit the ability of HDAC inhibitors to induce HIV-1 expression from an integrated virus. With effective antiretroviral therapy, newly expressed HIV-1 is incapable of reinfecting naive cells. With HIV-1 expression, one assumes the infected cell dies and there is a progressive reduction in the size of the reservoir. The concept was tested using the HDAC inhibitor valproic acid. However, valproic acid is weak in inducing HIV-1 from latency in vitro. As such, clinical trials revealed a small or no effect on reducing the number of latently infected T cells in the peripheral blood. However, the new HDAC inhibitors vorinostat, belinostat and givinostat are more effective at targeting specific HDACs for HIV-1 expression than valproic acid. Here, we review studies on HDAC inhibitor-induced expression of latent HIV-1, with an emphasis on new and specific HDAC inhibitors. With increased potency for HIV-1 expression as well as safety and ease of oral administration, new HDAC inhibitors offer a unique opportunity to deplete the latent reservoir. An additional benefit is the antiinflammatory properties of HDAC inhibitors, including downregulation of HIV-1 coreceptor expression. PMID:21424110

Matalon, Shay; Rasmussen, Thomas A; Dinarello, Charles A

2011-01-01

120

Monoubiquitination of filamin B regulates vascular endothelial growth factor-mediated trafficking of histone deacetylase 7.  

PubMed

Nucleocytoplasmic shuttling of class IIa of histone deacetylases (HDACs) is a key mechanism that controls cell fate and animal development. We have identified the filamin B (FLNB) as a novel HDAC7-interacting protein that is required for temporal and spatial regulation of vascular endothelial growth factor (VEGF)-mediated HDAC7 cytoplasmic sequestration. This interaction occurs in the cytoplasm and requires monoubiquitination of an evolutionarily conserved lysine 1147 (K1147) in the immunoglobulin (Ig)-like repeat 10 (R10) of FLNB and the nuclear localization sequence of HDAC7. Inhibition of protein kinase C (PKC) blocks VEGF-induced ubiquitination of FLNB and its interaction with HDAC7. Small interfering RNA (siRNA) knockdown of FLNB or ubiquitin (Ub) in human primary endothelial cells blocks VEGF-mediated cytoplasmic accumulation of HDAC7, reduces VEGF-induced expression of the HDAC7 target genes Mmp-10 and Nur77, and inhibits VEGF-induced vascular permeability. Using dominant negative mutants and rescue experiments, we demonstrate the functional significance of FLNB K1147 to interfere with the ability of phorbol myristate acetate (PMA) to promote FLNB-mediated cytoplasmic accumulation of HDAC7. Taken together, our data show that VEGF and PKC promote degradation-independent protein ubiquitination of FLNB to control intracellular trafficking of HDAC7. PMID:23401860

Su, Yu-Ting; Gao, Chengzhuo; Liu, Yu; Guo, Shuang; Wang, Anthony; Wang, Benlian; Erdjument-Bromage, Hediye; Miyagi, Masaru; Tempst, Paul; Kao, Hung-Ying

2013-04-01

121

Histone deacetylase-4 is required during early cranial neural crest development for generation of the zebrafish palatal skeleton  

PubMed Central

Background Histone deacetylase-4 (Hdac4) is a class II histone deacetylase that inhibits the activity of transcription factors. In humans, HDAC4 deficiency is associated with non-syndromic oral clefts and brachydactyly mental retardation syndrome (BDMR) with craniofacial abnormalities. Results We identify hdac4 in zebrafish and characterize its function in craniofacial morphogenesis. The gene is present as a single copy, and the deduced Hdac4 protein sequence shares all known functional domains with human HDAC4. The zebrafish hdac4 transcript is widely present in migratory cranial neural crest (CNC) cells of the embryo, including populations migrating around the eye, which previously have been shown to contribute to the formation of the palatal skeleton of the early larva. Embryos injected with hdac4 morpholinos (MO) have reduced or absent CNC populations that normally migrate medial to the eye. CNC-derived palatal precursor cells do not recover at the post-migratory stage, and subsequently we found that defects in the developing cartilaginous palatal skeleton correlate with reduction or absence of early CNC cells. Palatal skeletal defects prominently include a shortened, clefted, or missing ethmoid plate, and are associated with a shortening of the face of young larvae. Conclusions Our results demonstrate that Hdac4 is a regulator of CNC-derived palatal skeletal precursors during early embryogenesis. Cleft palate resulting from HDAC4 mutations in human patients may result from defects in a homologous CNC progenitor cell population. PMID:22676467

2012-01-01

122

Roles of histone deacetylases in epigenetic regulation: emerging paradigms from studies with inhibitors  

PubMed Central

The zinc-dependent mammalian histone deacetylase (HDAC) family comprises 11 enzymes, which have specific and critical functions in development and tissue homeostasis. Mounting evidence points to a link between misregulated HDAC activity and many oncologic and nononcologic diseases. Thus the development of HDAC inhibitors for therapeutic treatment garners a lot of interest from academic researchers and biotechnology entrepreneurs. Numerous studies of HDAC inhibitor specificities and molecular mechanisms of action are ongoing. In one of these studies, mass spectrometry was used to characterize the affinities and selectivities of HDAC inhibitors toward native HDAC multiprotein complexes in cell extracts. Such a novel approach reproduces in vivo molecular interactions more accurately than standard studies using purified proteins or protein domains as targets and could be very useful in the isolation of inhibitors with superior clinical efficacy and decreased toxicity compared to the ones presently tested or approved. HDAC inhibitor induced-transcriptional reprogramming, believed to contribute largely to their therapeutic benefits, is achieved through various and complex mechanisms not fully understood, including histone deacetylation, transcription factor or regulator (including HDAC1) deacetylation followed by chromatin remodeling and positive or negative outcome regarding transcription initiation. Although only a very low percentage of protein-coding genes are affected by the action of HDAC inhibitors, about 40% of noncoding microRNAs are upregulated or downregulated. Moreover, a whole new world of long noncoding RNAs is emerging, revealing a new class of potential targets for HDAC inhibition. HDAC inhibitors might also regulate transcription elongation and have been shown to impinge on alternative splicing. PMID:22414492

2012-01-01

123

Silencing Histone Deacetylase–Specific Isoforms Enhances Expression of Pluripotency Genes in Bovine Fibroblasts  

PubMed Central

Abstract Histone deacetylases (HDACs) catalyze deacetylation of histones that results in altered transcriptional activity. Inhibitors of HDACs have been shown to induce transcriptional changes that contribute positively to reprogramming somatic cells either by nuclear transfer or inducing a pluripotent state. However, the exact molecular mechanisms whereby HDAC inhibitors function and the specificity of the HDAC isoforms in cell reprogramming are not yet fully understood. Herein, we report the ability of individual isoform-specific HDACs to modulate endogenous expression of pluripotency-associated genes in bovine somatic cells. This in vitro study showed that a transient selective depletion of HDACs resulted in elevated mRNA levels of Oct-4, Sox2, and Nanog. In particular, we found that inhibition of specific HDAC isoforms using small interfering (si) RNA significantly increased expression of Nanog, a key factor required for totipotency induced by somatic cell nuclear transfer and for maintaining pluripotency in embryonic and induced pluripotent stem cells. Our study suggests that this gene might be the most susceptible to HDAC activity inhibition. Moreover, a regulatory role of the class III HDAC, SIRT3, on an Oct4–Sox2–Nanog transcriptional network was revealed. We observed the upregulation of pluripotency-related genes by depletion of SIRT3. SIRT3 is localized to mitochondria and is associated with energy metabolism processes, suggesting metabolic changes may be linked to reprogramming in bovine fibroblasts. In conclusion, we show that targeting selective HDACs can potentially be useful to enhance reprogramming and that sirtuins may play a pivotal role in somatic cell reprogramming by upregulating an Oct4–Sox2–Nanog transcriptional network. Dedifferentiating donor somatic cells by upregulating developmentally important genes through specific knockdown of epigenetic targets, in particular HDACs, may provide a path to improving livestock cloning and the in vitro production of pluripotent cells. PMID:24020699

Power, Rachel A.; Harkins, Lettie L.; Barnes, Christian W.; Strickler, Karen L.; Rim, Jong S.; Bondioli, Kenneth R.

2013-01-01

124

Histone Deacetylase Inhibitors in Malignant Pleural Mesothelioma  

PubMed Central

Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer of the mesothelium with only a limited range of treatment options that are largely ineffective in improving survival. Recent efforts have turned toward the analysis of specific, dysregulated biologic pathways for insight into new treatment targets. Epigenetic regulation of tumor suppressor genes through chromatin condensation and decondensation has emerged as an important mechanism that leads to tumorogenesis. A family of histone acetyltransferases and deacetylases regulates this balance, with the latter facilitating chromatin condensation, thus preventing gene transcription, resulting in the loss of heterozygosity of tumor suppressors. Inhibition of this process, coupled with a similar inhibition of nonhistone protein deacetylation, ultimately leads to the promotion of apoptosis, cell cycle arrest, and inhibition of angiogenesis. An increasing amount of preclinical data highlighting the effectiveness of histone deacetylase inhibition in MPM cell lines and mouse xenograft models has led to a number of early phase clinical trials in patients with MPM. The results of these efforts have led to a multicenter, randomized, placebo-controlled phase III study of the histone deacetylase inhibitor vorinostat in patients with advanced MPM, offering hope for a new and effective therapy in patients with this disease. PMID:20035240

Paik, Paul K.; Krug, Lee M.

2014-01-01

125

Histone Deacetylase Inhibition Reduces Pulmonary Vein Arrhythmogenesis through Calcium Regulation.  

PubMed

Pulmonary veins (PVs) play a critical role in the pathophysiology of atrial fibrillation (AF). Histone deacetylases (HDACs) are vital to calcium homeostasis and AF genesis. However, the electrophysiological effects of HDAC inhibition were unclear. This study evaluated whether HDAC inhibition can regulate PV electrical activity through calcium modulation. Whole-cell patch-clamp, confocal microscopic with fluorescence, and Western blot were used to evaluate electrophysiological characteristics and Ca(2+) dynamics in isolated rabbit PV cardiomyocytes with and without MPT0E014 (a pan HDAC inhibitor), MS-275 (HDAC1 and 3 inhibitor), and MC-1568 (HDAC4 and 6 inhibitor) for 5~8h. Atrial electrical activity and induced-AF (rapid atrial pacing and acetylcholine infusion) were measured in rabbits with and without MPT0E014 (10mg/kg treated for 5hours) in vivo. MPT0E014 (1?M)-treated PV cardiomyocytes (n=12) had slower beating rates (2.1±0.2 vs. 2.8±0.1Hz, p<0.05) than control PV cardiomyocytes. However, control (n=11) and MPT0E014 (1?M)-treated (n=12) SAN cardiomyocytes had similar beating rates (3.2±0.2 vs. 2.9±0.3Hz). MS-275-treated PV cardiomyocytes (n=12, 2.3±0.2Hz), but not MC-1568-treated PV cardiomyocytes (n=14, 3.1±0.3Hz) had slower beating rates than control PV cardiomocytes. MPT0E014-treated PV cardiomyocytes (n=14) had a lower frequency (2.4±0.6 vs. 0.3±0.1 spark/mm/s, p<0.05) of Ca(2+) sparks than control PV (n=17) cardiomyocytes. As compared to control, MPT0E014-treated PV cardiomyocytes had reduced Ca(2+) transient amplitudes, sodium-calcium exchanger currents, and ryanodine receptor expressions. Moreover, MPT0E014-treated rabbits had less AF and shorter AF duration than control rabbits. In conclusions, HDAC inhibition reduced PV arrhythmogenesis and AF inducibility with modulation on calcium homeostasis. PMID:25449511

Lkhagva, Baigalmaa; Chang, Shih-Lin; Chen, Yao-Chang; Kao, Yu-Hsun; Lin, Yung-Kuo; Chiu, Cindy Tzu-Hsuan; Chen, Shih-Ann; Chen, Yi-Jen

2014-10-01

126

Hydroxamic acid based histone deacetylase inhibitors with confirmed activity against the malaria parasite.  

PubMed

Recent studies have highlighted a key role in regulating gene transcription, in both eukaryotes and prokaryotes, by enzymes that control the acetylation and deacetylation of histones. In particular, inhibitors of histone deacetylases (HDAC-Is) have been shown effective in controlling the development of many parasites, such as the plasmodium of malaria. Here we report the results of a study aimed at evaluating antiparasitic effect of two classes of HDAC-Is bearing different zinc binding group (hydroxamic acid vs thiol). The study showed that only the hydroxamic acid based HDAC inhibitors were active, with Plasmodium falciparum being the most sensitive parasite, having from low double-digit to single-digit nanomolar range in vitro activities. Among three derivatives evaluated also in vivo, ST8086AA1 (8) effectively inhibited 88% of the development of Plasmodium falciparum. PMID:25563890

Giannini, Giuseppe; Battistuzzi, Gianfranco; Vignola, Davide

2015-02-01

127

Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease  

Microsoft Academic Search

Huntington's disease (HD) is an inherited, progressive neurological disorder that is caused by a CAG\\/polyglutamine repeat expansion and for which there is no effective therapy. Recent evidence indicates that transcriptional dysregulation may contribute to the molecular pathogenesis of this disease. Supporting this view, administration of histone deacetylase (HDAC) inhibitors has been shown to rescue lethality and photoreceptor neurodegeneration in a

Emma Hockly; Victoria M. Richon; Benjamin Woodman; Donna L. Smith; Xianbo Zhou; Eddie Rosa; Kirupa Sathasivam; Shabnam Ghazi-Noori; Amarbirpal Mahal; Philip A. S. Lowden; Joan S. Steffan; J. Lawrence Marsh; Leslie M. Thompson; Cathryn M. Lewis; Paul A. Marks; Gillian P. Bates

2003-01-01

128

The histone deacetylase inhibitor MS275 induces caspase-dependent apoptosis in B-cell chronic lymphocytic leukemia cells  

Microsoft Academic Search

MS-275 is a histone deacetylase (HDAC) inhibitor that has been reported to mediate its cytotoxic effect through generation of reactive oxygen species (ROS) in proliferating hematopoietic cell lines. We examined efficacy of MS-275 in nonproliferating chronic lymphocytic leukemia (CLL) cells from patients. In these cells, MS-275 demonstrated an in vitro LC50 that was one log lower than for normal mononuclear

D M Lucas; M E Davis; M R Parthun; A P Mone; S Kitada; K D Cunningham; E L Flax; J Wickham; J C Reed; J C Byrd; M R Grever

2004-01-01

129

Computational identification of novel histone deacetylase inhibitors by docking based QSAR.  

PubMed

Histone deacetylases (HDACs) are enzymes that modify chromatin structure and contribute to aberrant gene expression in cancer. A series compounds with well-assigned HDAC inhibitory activity was used for docking based 3D-QSAR analysis. The 3D-QSAR acquired had excellent correlation coefficient value (q2=0.753) and high Fisher ratio (F=300.2). A validated pharmacophore model (AAAPR) was employed for virtual screening. After manual selection, molecular docking and further refinement, six compounds with good absorption, distribution, metabolism, and excretion (ADME) properties were selected as potential HDAC inhibitors. Further, the molecular interactions of these inhibitors with the HDAC active site residues were discussed in detail. PMID:22521374

Nair, Syam B; Teli, Mahesh Kumar; Pradeep, H; Rajanikant, G K

2012-06-01

130

The interplay between microRNAs and histone deacetylases in neurological diseases  

PubMed Central

Neurological conditions, such as Alzheimer’s disease and stroke, represent a prevalent group of devastating illnesses with few treatments. Each of these diseases or conditions is in part characterized by the dysregulation of many genes, including those that code for microRNAs (miRNAs) and histone deacetylases (HDACs). Recently, a complex relationship has been uncovered linking miRNAs and HDACs and their ability to regulate one another. This provides a new avenue for potential therapeutics as the ability to reinstate a careful balance between miRNA and HDACs has lead to improved outcomes in a number of in vitro and in vivo models of neurological conditions. In this review, we will discuss recent findings on the interplay between miRNAs and HDACs and its implications for pathogenesis and treatment of neurological conditions, including amyotrophic lateral sclerosis, Alzheimer’s disease, Huntington’s disease and stroke. PMID:24681158

Bourassa, Megan W.; Ratan, Rajiv R.

2015-01-01

131

Benefits of histone deacetylase inhibitors for acute brain injury; a systematic review of animal studies  

PubMed Central

Drugs that inhibit histone deacetylase (HDAC) activities have enormous potential as neuroprotective agents. We performed a systematic review of controlled animal studies that administered known inhibitors of the zinc-dependent HDACs before and/or after acute cerebral injury and assessed anatomic/functional outcomes. Relevant studies were found by searching PubMed, Embase and Web of Science. From more than 100 identified publications, those data meeting specific criteria were analyzed using the Cochrane Review Manager software. A beneficial effect of administering HDAC inhibitors was seen in studies involving cerebral ischemia or non-ischemic models of acute cerebral injury. Specific studies assessed efficacy when drug was administered up to 14 days prior to, and 14 days following, the onset of cerebral injury. This systematic review provides objective evidence of a neuroprotective role for drugs that inhibit HDACs and highlights particular areas that require further experimental investigation. PMID:20831615

Gibson, Claire L.; Murphy, Sean P.

2010-01-01

132

Dosage-dependent tumor suppression by histone deacetylases 1 and 2 through regulation of c-Myc collaborating genes and p53 function  

PubMed Central

Histone deacetylases (HDACs) are epigenetic erasers of lysine-acetyl marks. Inhibition of HDACs using small molecule inhibitors (HDACi) is a potential strategy in the treatment of various diseases and is approved for treating hematological malignancies. Harnessing the therapeutic potential of HDACi requires knowledge of HDAC-function in vivo. Here, we generated a thymocyte-specific gradient of HDAC-activity using compound conditional knockout mice for Hdac1 and Hdac2. Unexpectedly, gradual loss of HDAC-activity engendered a dosage-dependent accumulation of immature thymocytes and correlated with the incidence and latency of monoclonal lymphoblastic thymic lymphomas. Strikingly, complete ablation of Hdac1 and Hdac2 abrogated lymphomagenesis due to a block in early thymic development. Genomic, biochemical and functional analyses of pre-leukemic thymocytes and tumors revealed a critical role for Hdac1/Hdac2-governed HDAC-activity in regulating a p53-dependent barrier to constrain Myc-overexpressing thymocytes from progressing into lymphomas by regulating Myc-collaborating genes. One Myc-collaborating and p53-suppressing gene, Jdp2, was derepressed in an Hdac1/2-dependent manner and critical for the survival of Jdp2-overexpressing lymphoma cells. Although reduced HDAC-activity facilitates oncogenic transformation in normal cells, resulting tumor cells remain highly dependent on HDAC-activity, indicating that a critical level of Hdac1 and Hdac2 governed HDAC-activity is required for tumor maintenance. PMID:23327920

Heideman, Marinus R.; Wilting, Roel H.; Yanover, Eva; Velds, Arno; de Jong, Johann; Kerkhoven, Ron M.; Jacobs, Heinz; Wessels, Lodewyk F.

2013-01-01

133

Clinical studies of histone deacetylase inhibitors.  

PubMed

Over the last 5 years, a plethora of histone deacetylase inhibitors (HDACi) have been evaluated in clinical trials. These drugs have in common the ability to hyperacetylate both histone and nonhistone targets, resulting in a variety of effects on cancer cells, their microenvironment, and immune responses. To date, responses with single agent HDACi have been predominantly observed in advanced hematologic malignancies including T-cell lymphoma, Hodgkin lymphoma, and myeloid malignancies. Therefore, in this review we focus upon hematologic malignancies. Generally HDACi are well tolerated with the most common acute toxicities being fatigue, gastrointestinal, and transient cytopenias. Of note, few patients have been treated for prolonged periods of time and little is known about long-term toxicities. The use of the biomarker of histone hyperacetylation has been useful as a guide to target specificity, but generally does not predict for response and the search for more clinically relevant biomarkers must continue. PMID:19509172

Prince, H Miles; Bishton, Mark J; Harrison, Simon J

2009-06-15

134

Histone deacetylase regulation of immune gene expression in tumor cells  

Microsoft Academic Search

Epigenetic modifications of chromatin, such as histone acetylation, are involved in repression of tumor antigens and multiple\\u000a immune genes that are thought to facilitate tumor escape. The status of acetylation in a cell is determined by the balance\\u000a of the activities of histone acetyltransferases and histone deacetylases. Inhibitors of histone deacetylase (HDACi) can enhance\\u000a the expression of immunologically important molecules

A. Nazmul H. Khan; Thomas B. Tomasi

2008-01-01

135

Histone Deacetylase Classes I and II Regulate Kaposi's Sarcoma-Associated Herpesvirus Reactivation  

PubMed Central

In primary effusion lymphoma (PEL) cells infected with latent Kaposi's sarcoma-associated herpesvirus (KSHV), the promoter of the viral lytic switch gene, Rta, is organized into bivalent chromatin, similar to cellular developmental switch genes. Histone deacetylase (HDAC) inhibitors (HDACis) reactivate latent KSHV and dramatically remodel the viral genome topology and chromatin architecture. However, reactivation is not uniform across a population of infected cells. We sought to identify an HDACi cocktail that would uniformly reactivate KSHV and reveal the regulatory HDACs. Using HDACis with various specificities, we found that class I HDACis were sufficient to reactivate the virus but differed in potency. Valproic acid (VPA) was the most effective HDACi, inducing lytic cycle gene expression in 75% of cells, while trichostatin A (TSA) induced less widespread lytic gene expression and inhibited VPA-stimulated reactivation. VPA was only slightly superior to TSA in inducing histone acetylation of Rta's promoter, but only VPA induced significant production of infectious virus, suggesting that HDAC regulation after Rta expression has a dramatic effect on reactivation progression. Ectopic HDACs 1, 3, and 6 inhibited TPA-stimulated KSHV reactivation. Surprisingly, ectopic HDACs 1 and 6 stimulated reactivation independently, suggesting that the stoichiometries of HDAC complexes are critical for the switch. Tubacin, a specific inhibitor of the ubiquitin-binding, proautophagic HDAC6, also inhibited VPA-stimulated reactivation. Immunofluorescence indicated that HDAC6 is expressed diffusely throughout latently infected cells, but its expression level and nuclear localization is increased during reactivation. Overall, our data suggest that inhibition of HDAC classes I and IIa and maintenance of HDAC6 (IIb) activity are required for optimal KSHV reactivation. PMID:24227836

Shin, Hye Jin; DeCotiis, Jennifer; Giron, Mario; Palmeri, Diana

2014-01-01

136

Histone Deacetylases Control Neurogenesis in Embryonic Brain by Inhibition of BMP2/4 Signaling  

PubMed Central

Background Histone-modifying enzymes are essential for a wide variety of cellular processes dependent upon changes in gene expression. Histone deacetylases (HDACs) lead to the compaction of chromatin and subsequent silencing of gene transcription, and they have recently been implicated in a diversity of functions and dysfunctions in the postnatal and adult brain including ocular dominance plasticity, memory consolidation, drug addiction, and depression. Here we investigate the role of HDACs in the generation of neurons and astrocytes in the embryonic brain. Principal Findings As a variety of HDACs are expressed in differentiating neural progenitor cells, we have taken a pharmacological approach to inhibit multiple family members. Inhibition of class I and II HDACs in developing mouse embryos with trichostatin A resulted in a dramatic reduction in neurogenesis in the ganglionic eminences and a modest increase in neurogenesis in the cortex. An identical effect was observed upon pharmacological inhibition of HDACs in in vitro-differentiating neural precursors derived from the same brain regions. A reduction in neurogenesis in ganglionic eminence-derived neural precursors was accompanied by an increase in the production of immature astrocytes. We show that HDACs control neurogenesis by inhibition of the bone morphogenetic protein BMP2/4 signaling pathway in radial glial cells. HDACs function at the transcriptional level by inhibiting and promoting, respectively, the expression of Bmp2 and Smad7, an intracellular inhibitor of BMP signaling. Inhibition of the BMP2/4 signaling pathway restored normal levels of neurogenesis and astrogliogenesis to both ganglionic eminence- and cortex-derived cultures in which HDACs were inhibited. Conclusions Our results demonstrate a transcriptionally-based regulation of BMP2/4 signaling by HDACs both in vivo and in vitro that is critical for neurogenesis in the ganglionic eminences and that modulates cortical neurogenesis. The results also suggest that HDACs may regulate the developmental switch from neurogenesis to astrogliogenesis that occurs in late gestation. PMID:18628975

Shakèd, Maya; Weissmüller, Kathrin; Svoboda, Hanno; Hortschansky, Peter; Nishino, Norikazu; Wölfl, Stefan; Tucker, Kerry L.

2008-01-01

137

Modulation of Histone Deacetylase Activity by Dietary Isothiocyanates and Allyl Sulfides: Studies with Sulforaphane and Garlic Organosulfur Compounds  

PubMed Central

Histone deacetylase (HDAC) inhibitors reactivate epigenetically-silenced genes in cancer cells, triggering cell cycle arrest and apoptosis. Recent evidence suggests that dietary constituents can act as HDAC inhibitors, such as the isothiocyanates found in cruciferous vegetables and the allyl compounds present in garlic. Broccoli sprouts are a rich source of sulforaphane (SFN), an isothiocyanate that is metabolized via the mercapturic acid pathway and inhibits HDAC activity in human colon, prostate, and breast cancer cells. In mouse preclinical models, SFN inhibited HDAC activity and induced histone hyperacetylation coincident with tumor suppression. Inhibition of HDAC activity also was observed in circulating peripheral blood mononuclear cells obtained from people who consumed a single serving of broccoli sprouts. Garlic organosulfur compounds can be metabolized to allyl mercaptan (AM), a competitive HDAC inhibitor that induced rapid and sustained histone hyperacetylation in human colon cancer cells. Inhibition of HDAC activity by AM was associated with increased histone acetylation and Sp3 transcription factor binding to the promoter region of the P21WAF1 gene, resulting in elevated p21 protein expression and cell cycle arrest. Collectively, the results from these studies, and others reviewed herein, provide new insights into the relationships between reversible histone modifications, diet, and cancer chemoprevention. PMID:19197985

Nian, Hui; Delage, Barbara; Ho, Emily; Dashwood, Roderick H.

2009-01-01

138

Expression of Histone Deacetylases in Diffuse Large B-cell Lymphoma and Its Clinical Significance  

PubMed Central

Background: Histone deacetylase inhibitors are a new class of drugs used in treatment of malignant tumors. Diffuse large B-cell lymphoma (DLBCL) is the most common type of B-cell lymphoma, and it accounts for more than 40% of all B-cell lymphomas. In this study, we aimed to determine the expression patterns of histone deacetylases (HDACs) in DLBCL, to examine whether HDAC expression patterns differ among cases, and to assess whether these findings have clinical significance. Materials and methods: We selected 91 cases of DLBCL diagnosed at St. Vincent Hospital, The Catholic University of Korea, from 2001-2012. We performed a pathology slide review and collected clinical data including age, sex, tumor site, survival time, and mortality. Immunohistochemical analysis was performed using primary antibodies for HDACs, including HDAC1 and 2 of class I, HDAC4 and 5 of class IIa, and HDAC6 of class IIb. Expression site was determined to be nuclear, cytoplasmic, or both. Staining intensities were graded as low and high. We assessed correlations between HDAC expression levels and clinical data and survival analysis. Results: Of the 91 cases examined, 46 (50.5%) were men and 45 (49.5%) were women. Most of the patients were elderly, and 74 (81.3%) cases were older than 46 y. Forty-six (50.5%) cases showed lymph node involvement, and 45 (49.5%) cases showed lymphoma at extranodal sites. In nodal lymphoma, staining was strongly positive for HDAC2, whereas staining was weak or negative for HDAC4; however, there was no significant correlation with survival. But nodal lymphoma cases with high nuclear expression of HDAC2 and nodal lymphoma cases with high nuclear expression of HDAC2 and low nuclear expression of HDAC4 showed significantly shorter survival times compared with other cases. Conclusions: High nuclear expression of HDAC2 may play an important role in survival of DLBCL patients, especially in those with nodal lymphoma, which is associated with a shorter survival time. Our results may have important implications for treatment of DLBCL by epigenetic regulation. PMID:25076845

Lee, Sung Hak; Yoo, Changyoung; Im, Soyoung; Jung, Ji-Han; Choi, Hyun Joo; Yoo, Jinyoung

2014-01-01

139

Unique functional roles for class I and class II histone deacetylases in central nervous system development and function  

PubMed Central

Non-specific pharmacological inhibition of the histone deacetylase (HDAC) family of enzymes has largely beneficial effects in a variety of diverse contexts including cancer, cognitive function, and neurodegeneration. This review will discuss the role of individual HDAC isoforms in brain function during development and in the adult. Importantly class I and class II HDACs exhibit distinct cellular and subcellular expression patterns and utilize different signaling pathways to influence their substrates. Moreover, dissociable phenotypic outcomes emerge following manipulation of individual HDACs in the brain. To date, pharmacological inhibitors capable of targeting individual HDACs have proven difficult to develop, an obstacle that must be overcome to unlock the substantial clinical promise of manipulating endogenous HDAC isoforms in the central nervous system. PMID:23466417

Morris, Michael J.; Monteggia, Lisa M.

2013-01-01

140

MiR-145 functions as a tumor suppressor by directly targeting histone deacetylase 2 in liver cancer.  

PubMed

Aberrant regulation of histone deacetylase 2 (HDAC2) plays a pivotal role in the development of hepatocellular carcinoma (HCC), but, the underlying mechanism leading to HDAC2 overexpression is not well understood. We performed microRNA (miRNA) profiling analysis in a subset of HCCs, and identified four down-regulated miRNAs that may target HDAC2 in HCC. Ectopic expression of miRNA mimics evidenced that miR-145 suppresses HDAC2 expression in HCC cells. This treatment repressed cancer cell growth and recapitulated HDAC2 knockdown effects on HCC cells. In conclusion, we suggest that loss or suppression of miR-145 may cause aberrant overexpression of HDAC2 and promote HCC tumorigenesis. PMID:23499894

Noh, Ji Heon; Chang, Young Gyoon; Kim, Min Gyu; Jung, Kwang Hwa; Kim, Jeong Kyu; Bae, Hyun Jin; Eun, Jung Woo; Shen, Qingyu; Kim, Seung-Jin; Kwon, So Hee; Park, Won Sang; Lee, Jung Young; Nam, Suk Woo

2013-07-28

141

Disrupted ectodermal organ morphogenesis in mice with a conditional histone deacetylase 1, 2 deletion in the epidermis  

PubMed Central

Histone deacetylases (HDAC) are present in the epidermal layer of the skin, outer root sheath and hair matrix. To investigate how histone acetylation affects skin morphogenesis and homeostasis, mice were generated with a K14 promoter-mediated reduction of Hdac1 or Hdac2. The skin of HDAC1 null (K14-Cre Hdac1cKO/cKO) mice exhibited a spectrum of lesions including irregularly thickened interfollicular epidermis, alopecia, hair follicle dystrophy, claw dystrophy, and abnormal pigmentation. Hairs are sparse, short and intermittently coiled. The distinct pelage hair types are lost. During the first hair cycle, hairs are lost and replaced by dystrophic hair follicles with dilated infundibulae. The dystrophic hair follicle epithelium is stratified and positive for K14, involucrin, and TRP63 but negative for K10. Some dystrophic follicles are K15 positive but mature hair fiber keratins are absent. The digits form extra hyper-pigmented claws on the lateral sides. Hyper-pigmentation is observed in the interfollicular epithelium, the tail, and the feet. Hdac1 and Hdac2 dual transgenic mice (K14-Cre Hdac1cKO/cKO Hdac2+/cKO) have similar but more obvious abnormalities. These results show that suppression of epidermal HDAC activity leads to improper ectodermal organ morphogenesis, disrupted hair follicle regeneration and homeostasis, as well as indirect effects on pigmentation. PMID:23792463

Hughes, Michael W.; Jiang, Ting-Xin; Lin, Sung-Jan; Leung, Yvonne; Kobielak, Krzysztof; Widelitz, Randall B.; Chuong, Cheng Ming

2013-01-01

142

Disrupted ectodermal organ morphogenesis in mice with a conditional histone deacetylase 1, 2 deletion in the epidermis.  

PubMed

Histone deacetylases (HDACs) are present in the epidermal layer of the skin, outer root sheath, and hair matrix. To investigate how histone acetylation affects skin morphogenesis and homeostasis, mice were generated with a K14 promoter-mediated reduction of Hdac1 or Hdac2. The skin of HDAC1 null (K14-Cre Hdac1(cKO/cKO)) mice exhibited a spectrum of lesions, including irregularly thickened interfollicular epidermis, alopecia, hair follicle dystrophy, claw dystrophy, and abnormal pigmentation. Hairs are sparse, short, and intermittently coiled. The distinct pelage hair types are lost. During the first hair cycle, hairs are lost and replaced by dystrophic hair follicles with dilated infundibulae. The dystrophic hair follicle epithelium is stratified and is positive for K14, involucrin, and TRP63, but negative for keratin 10. Some dystrophic follicles are K15 positive, but mature hair fiber keratins are absent. The digits form extra hyperpigmented claws on the lateral sides. Hyperpigmentation is observed in the interfollicular epithelium, the tail, and the feet. Hdac1 and Hdac2 dual transgenic mice (K14-Cre Hdac1(cKO/cKO) Hdac2(+/cKO)) have similar but more obvious abnormalities. These results show that suppression of epidermal HDAC activity leads to improper ectodermal organ morphogenesis and disrupted hair follicle regeneration and homeostasis, as well as indirect effects on pigmentation. PMID:23792463

Hughes, Michael W; Jiang, Ting-Xin; Lin, Sung-Jan; Leung, Yvonne; Kobielak, Krzysztof; Widelitz, Randall B; Chuong, Cheng M

2014-01-01

143

Entinostat is a histone deacetylase inhibitor selective for class 1 histone deacetylases and activates HIV production from latently infected primary T cells  

PubMed Central

Objectives To compare the potency, toxicity and mechanism of action of multiple histone deacetylase inhibitors (HDACi) in activating HIV production from latency. Design In-vitro analysis of HDACi in a primary T-cell model of HIV latency and latently infected cell lines. Methods Latently infected chemokine ligand 19 (CCL19)-treated CD4+ T cells and the latently infected cell lines ACH2 and J-Lat were treated with a panel of HDACi, including entinostat, vorinostat, panonbinostat and MCT3. Viral production and cell viability were compared. Expression of cellular HDACs was measured by western blot and PCR. Association of HDACs with the HIV long-terminal repeat (LTR) using latently infected CCL19-treated primary CD4+ T cells in the presence and absence of specific HDACi was determined by chromatin immunoprecipitation (ChIP). Results We demonstrated considerable variation in the potency and toxicity of HDACi in latently infected primary CD4+ T cells and cell lines. All HDACi tested activated HIV production in latently infected primary T cells with greatest potency demonstrated with entinostat and vorinostat and greatest toxicity with panobinostat. Following the addition of HDACi in vitro, there were no changes in markers of T-cell activation or expression of the HIV coreceptors chemokine (C-X-C motif) receptor 4 (CXCR4) or chemokine (C-C motif) receptor type 5 (CCR5). ChIP analysis of latently infected CCL19-treated primary CD4+ T cells showed binding by HDAC1, HDAC2 and HDAC3 to the LTR with removal of HDAC1 and HDAC2 following treatment with the HDACi vorinostat and HDAC1 only following treatment with entinostat. Conclusion The HDACi entinostat, selective for inhibition of class I HDACs, induced virus expression in latently infected primary CD4+ T cells making this compound an attractive novel option for future clinical trials. PMID:24189584

Wightman, Fiona; Lu, Hao K.; Solomon, Ajantha E.; Saleh, Suha; Harman, Andrew N.; Cunningham, Anthony L.; Gray, Lachlan; Churchill, Melissa; Cameron, Paul U.; Dear, Anthony E.; Lewin, Sharon R.

2014-01-01

144

Expression and functional analysis of the plant-specific histone deacetylase HDT701 in rice  

PubMed Central

Reversible histone acetylation and deacetylation at the N-terminus of histone tails play a crucial role in regulating eukaryotic gene activity. Acetylation of core histones is associated with gene activation, whereas deacetylation of histone is often correlated with gene repression. The level of histone acetylation is antagonistically catalyzed by histone acetyltransferases citation(HATs) and histone deacetylases (HDACs). In this work, we examined the subcellular localization, expression pattern and function of HDT701, a member of the plant-specific HD2-type histone deacetylase in rice. HDT701 is localized at the subcellular level in the nucleus. Histochemical GUS-staining analysis revealed that HDT701 is constitutively expressed throughout the life cycle of rice. Overexpression of HDT701 in rice decreases ABA, salt and osmotic stress resistance during seed germination. Delayed seed germination of HDT701 overexpression lines is associated with decreased histone H4 acetylation and down-regulated expression of GA biosynthetic genes. Moreover, overexpression of HDT701 in rice enhances salt and osmotic stress resistance during the seedling stage. Taken together, our findings suggested that HDT701 may play an important role in regulating seed germination in response to abiotic stresses in rice. PMID:25653654

Zhao, Jinhui; Zhang, Jianxia; Zhang, Wei; Wu, Kunlin; Zheng, Feng; Tian, Lining; Liu, Xuncheng; Duan, Jun

2015-01-01

145

Inhibition of histone deacetylase 2 mitigates profibrotic TGF-?1 responses in fibroblasts derived from Peyronie's plaque.  

PubMed

Epigenetic modifications, such as histone acetylation/deacetylation, have been shown to play a role in the pathogenesis of fibrotic disease. Peyronie's disease (PD) is a localized fibrotic process of the tunica albuginea, which leads to penile deformity. This study was undertaken to determine the anti-fibrotic effect of small interfering RNA (siRNA)-mediated silencing of histone deacetylase 2 (HDAC2) in primary fibroblasts derived from human PD plaque. PD fibroblasts were pre-treated with HDAC2 siRNA and then stimulated with transforming growth factor-?1 (TGF-?1). Protein was extracted from treated fibroblasts for Western blotting and the membranes were probed with antibody to phospho-Smad2/Smad2, phospho-Smad3/Smad3, smooth muscle ?-actin and extracellular matrix proteins, including plasminogen activator inhibitor-1, fibronectin, collagen I and collagen IV. We also performed immunocytochemistry to detect the expression of extracellular matrix proteins and to examine the effect of HDAC2 siRNA on the TGF-?1-induced nuclear translocation of Smad2/3 in fibroblasts. Knockdown of HDAC2 in PD fibroblasts abrogated TGF-?1-induced extracellular matrix production by blocking TGF-?1-induced phosphorylation and nuclear translocation of Smad2 and Smad3, and by inhibiting TGF-?1-induced transdifferentiation of fibroblasts into myofibroblasts. Decoding the individual function of the HDAC isoforms by use of siRNA technology, preferably siRNA for HDAC2, may lead to the development of specific and safe epigenetic therapies for PD. PMID:23770939

Ryu, Ji-Kan; Kim, Woo-Jean; Choi, Min-Ji; Park, Jin-Mi; Song, Kang-Moon; Kwon, Mi-Hye; Das, Nando-Dulal; Kwon, Ki-Dong; Batbold, Dulguun; Yin, Guo-Nan; Suh, Jun-Kyu

2013-09-01

146

Inhibition of histone deacetylase 2 mitigates profibrotic TGF-?1 responses in fibroblasts derived from Peyronie's plaque  

PubMed Central

Epigenetic modifications, such as histone acetylation/deacetylation, have been shown to play a role in the pathogenesis of fibrotic disease. Peyronie's disease (PD) is a localized fibrotic process of the tunica albuginea, which leads to penile deformity. This study was undertaken to determine the anti-fibrotic effect of small interfering RNA (siRNA)-mediated silencing of histone deacetylase 2 (HDAC2) in primary fibroblasts derived from human PD plaque. PD fibroblasts were pre-treated with HDAC2 siRNA and then stimulated with transforming growth factor-?1 (TGF-?1). Protein was extracted from treated fibroblasts for Western blotting and the membranes were probed with antibody to phospho-Smad2/Smad2, phospho-Smad3/Smad3, smooth muscle ?-actin and extracellular matrix proteins, including plasminogen activator inhibitor-1, fibronectin, collagen I and collagen IV. We also performed immunocytochemistry to detect the expression of extracellular matrix proteins and to examine the effect of HDAC2 siRNA on the TGF-?1-induced nuclear translocation of Smad2/3 in fibroblasts. Knockdown of HDAC2 in PD fibroblasts abrogated TGF-?1-induced extracellular matrix production by blocking TGF-?1-induced phosphorylation and nuclear translocation of Smad2 and Smad3, and by inhibiting TGF-?1-induced transdifferentiation of fibroblasts into myofibroblasts. Decoding the individual function of the HDAC isoforms by use of siRNA technology, preferably siRNA for HDAC2, may lead to the development of specific and safe epigenetic therapies for PD. PMID:23770939

Ryu, Ji-Kan; Kim, Woo-Jean; Choi, Min-Ji; Park, Jin-Mi; Song, Kang-Moon; Kwon, Mi-Hye; Das, Nando-Dulal; Kwon, Ki-Dong; Batbold, Dulguun; Yin, Guo-Nan; Suh, Jun-Kyu

2013-01-01

147

The Antiparasitic Clioquinol Induces Apoptosis in Leukemia and Myeloma Cells by Inhibiting Histone Deacetylase Activity*  

PubMed Central

The antiparasitic clioquinol (CQ) represents a class of novel anticancer drugs by interfering with proteasome activity. In the present study, we found that CQ induced blood cancer cell apoptosis by inhibiting histone deacetylases (HDACs). CQ accumulated the acetylation levels of several key proteins including histone H3 (H3), p53, HSP90, and ?-tubulin. In the mechanistic study, CQ was found to down-regulate HDAC1, -3, -4, and -5 in both myeloma and leukemia cells. Computer modeling analysis revealed that CQ was well docked into the active pocket of the enzyme, where the oxygen and nitrogen atoms in CQ formed stable coordinate bonds with the zinc ion, and the hydroxyl group from CQ formed an effective hydrogen bond with Asp-267. Moreover, co-treatment with CQ and zinc/copper chloride led to decreased Ac-H3. Furthermore, CQ inhibited the activity of Class I and IIa HDACs in the cell-free assays, demonstrating that CQ interfered with HDAC activity. By inhibiting HDAC activity, CQ induced expression of p21, p27, and p53, cell cycle arrest at G1 phase, and cell apoptosis. This study suggested that the HDAC enzymes are targets of CQ, which provided a novel insight into the molecular mechanism of CQ in the treatment of hematological malignancies. PMID:24114842

Cao, Biyin; Li, Jie; Zhu, Jingyu; Shen, Mingyun; Han, Kunkun; Zhang, Zubin; Yu, Yang; Wang, Yali; Wu, Depei; Chen, Suning; Sun, Aining; Tang, Xiaowen; Zhao, Yun; Qiao, Chunhua; Hou, Tingjun; Mao, Xinliang

2013-01-01

148

A Conserved Gammaherpesvirus Protein Kinase Targets Histone Deacetylases 1 and 2 To Facilitate Viral Replication in Primary Macrophages  

PubMed Central

Gammaherpesviruses are ubiquitious pathogens that establish lifelong infection and are associated with several malignancies. All gammaherpesviruses encode a conserved protein kinase that facilitates viral replication and chronic infection and thus represents an attractive therapeutic target. In this study, we identify a novel function of gammaherpesvirus protein kinase as a regulator of class I histone deacetylases (HDAC). Mouse gammaherpesvirus 68 (MHV68)-encoded protein kinase orf36 interacted with HDAC1 and 2 and prevented association of these HDACs with the viral promoter driving expression of RTA, a critical immediate early transcriptional activator. Furthermore, the ability to interact with HDAC1 and 2 was not limited to the MHV68 orf36, as BGLF4, a related viral protein kinase encoded by Epstein-Barr virus, interacted with HDAC1 in vitro. Importantly, targeting of HDAC1 and 2 by orf36 was independent of the kinase's enzymatic activity. Additionally, orf36 expression, but not its enzymatic activity, induced changes in the global deacetylase activity observed in infected primary macrophages. Combined deficiency of HDAC1 and 2 rescued attenuated replication and viral DNA synthesis of the orf36 null MHV68 mutant, indicating that the regulation of HDAC1 and 2 by orf36 was relevant for viral replication. Understanding the mechanism by which orf36 facilitates viral replication, including through HDAC targeting, will facilitate the development of improved therapeutics against gammaherpesvirus kinases. PMID:23616648

Mounce, Bryan C.; Mboko, Wadzanai P.; Bigley, Tarin M.; Terhune, Scott S.

2013-01-01

149

Histone Deacetylase Inhibitors from Burkholderia Thailandensis  

PubMed Central

Bioactivity guided fractionation of an extract of Burkholderia thailandensis led to the isolation and identification of a new cytotoxic depsipeptide and its dimer. Both compounds potently inhibited the function of histone deacetylases 1 and 4. The monomer, spiruchostatin C (2), was tested side-by-side with the clinical depsipeptide FK228 (1, Istodax®, romidepsin) in a murine hollow fiber assay consisting of 12 implanted tumor cell lines. Spiruchostatin C (2) showed good activity towards LOX IMVI melanoma cells and NCI-H522 non small cell lung cancer cells. Overall, however, FK228 (1) showed a superior in vivo antitumor profile compared to the new compound. PMID:21967146

Klausmeyer, Paul; Shipley, Suzanne; Zuck, Karina M.; McCloud, Thomas G.

2011-01-01

150

Histone deacetylase 8 suppresses osteogenic differentiation of bone marrow stromal cells by inhibiting histone H3K9 acetylation and RUNX2 activity.  

PubMed

Bone marrow stromal cells (BMSCs) are multipotent progenitor cells with capacities to differentiate into the various cell types and hold great promise in regenerative medicine. The regulatory roles of histone deacetylases (HDACs) in osteoblast differentiation process have been increasingly recognized; however, little is known about the precise roles of HDAC8 in the osteogenic differentiation of BMSCs. Herein we aimed to investigate the roles of HDAC8 in the osteogenic differentiation of rat BMSCs by pharmacological and genetic manipulations in vitro. During osteogenic differentiation of BMSCs, pharmacological inhibition of HDAC8 by HDAC inhibitor valproic acid (VPA) promoted the level of histone H3 lysine 9 acetylation (H3K9Ac) and significantly enhanced the expression of osteogenesis-related genes Runx2, Osterix, osteocalcin (OCN), osteopontin (OPN) and alkaline phosphatase (ALP). Similarly, knockdown of HDAC8 using short interfering RNA triggered H3K9Ac and enhanced osteogenic differentiation of BMSCs, largely phenocopied the effects of VPA-mediated HDAC8 depletion. However, enforced expression of HDAC8 significantly reduced the level of H3K9Ac and inhibited osteogenic differentiation of BMSCs, which can be attenuated by VPA addition. Mechanistically, HDAC8 suppressed osteogenesis-related genes expression by removing the acetylation of histone H3K9, thus leading to transcriptional inhibition during osteogenic differentiation of BMSCs. Importantly, we found that HDAC8 physically associated with Runx2 to repress its transcriptional activity and this association decreased when BMSCs underwent osteogenic differentiation. Taken together, these results indicate that epigenetic regulation of Runx2 by HDAC8-mediated histone H3K9 acetylation is required for the proper osteogenic differentiation of BMSCs. PMID:25019367

Fu, Yu; Zhang, Ping; Ge, Jie; Cheng, Jie; Dong, Weijie; Yuan, Hua; Du, Yifei; Yang, Mifang; Sun, Ruoxing; Jiang, Hongbing

2014-09-01

151

Inhibition of LSD1 sensitizes glioblastoma cells to histone deacetylase inhibitors.  

PubMed

Glioblastoma multiforme (GBM) is a particularly aggressive brain tumor and remains a clinically devastating disease. Despite innovative therapies for the treatment of GBM, there has been no significant increase in patient survival over the past decade. Enzymes that control epigenetic alterations are of considerable interest as targets for cancer therapy because of their critical roles in cellular processes that lead to oncogenesis. Several inhibitors of histone deacetylases (HDACs) have been developed and tested in GBM with moderate success. We found that treatment of GBM cells with HDAC inhibitors caused the accumulation of histone methylation, a modification removed by the lysine specific demethylase 1 (LSD1). This led us to examine the effects of simultaneously inhibiting HDACs and LSD1 as a potential combination therapy. We evaluated induction of apoptosis in GBM cell lines after combined inhibition of LSD1 and HDACs. LSD1 was inhibited by targeted short hairpin RNA or pharmacological means and inhibition of HDACs was achieved by treatment with either vorinostat or PCI-24781. Caspase-dependent apoptosis was significantly increased (>2-fold) in LSD1-knockdown GBM cells treated with HDAC inhibitors. Moreover, pharmacologically inhibiting LSD1 with the monoamine oxidase inhibitor tranylcypromine, in combination with HDAC inhibitors, led to synergistic apoptotic cell death in GBM cells; this did not occur in normal human astrocytes. Taken together, these results indicate that LSD1 and HDACs cooperate to regulate key pathways of cell death in GBM cell lines but not in normal counterparts, and they validate the combined use of LSD1 and HDAC inhibitors as a therapeutic approach for GBM. PMID:21653597

Singh, Melissa M; Manton, Christa A; Bhat, Krishna P; Tsai, Wen-Wei; Aldape, Kenneth; Barton, Michelle C; Chandra, Joya

2011-08-01

152

Msx3 protein recruits histone deacetylase to down-regulate the Msx1 promoter.  

PubMed Central

Msx1 promoter is known to be repressed by Msx1 protein [Shetty, Takahashi, Matsui, Iyengar and Raghow (1999) Biochem. J. 339, 751-758]. We show that in the transiently transfected C(2)C(12) myoblasts, co-expression of Msx3 also causes potent repression of Msx1 promoter that can be relieved by exogenous expression of cAMP-response-element-binding protein-binding protein (CBP) and p300 in a dose-dependent manner. Co-immunoprecipitation and Western blot analyses revealed that Msx3 interacts with CBP and p300 and this interaction significantly decreases the histone acetyltransferase (HAT) activity of both proteins. We also discovered that Msx3-mediated repression of Msx1 promoter is synergized by the exogenous co-expression of histone deacetylase 1 (HDAC1). Furthermore, the repression of Msx1 promoter by Msx3 could be relieved by treating transfected cells with trichostatin A, an inhibitor of HDAC(s). Finally, we show that Msx3 and HDAC1 can be co-immunoprecipitated in a complex that does not contain CBP and that Msx3 and HDAC1 proteins are co-localized in the nucleus. Taken together, our results strongly suggest that two distinct multiprotein complexes are present within the nuclei of C(2)C(12) cells: one containing Msx3 and HDAC(s) and another containing Msx3 and CBP and/or p300. On the basis of these results, we propose a dual mechanism of repression by Msx3 protein that involves the squelching of the HAT activity of co-activators, CBP and p300, and recruitment of HDAC(s). PMID:11115394

Mehra-Chaudhary, R; Matsui, H; Raghow, R

2001-01-01

153

HDAC inhibition imparts beneficial transgenerational effects in Huntington's disease mice via altered DNA and histone methylation.  

PubMed

Increasing evidence has demonstrated that epigenetic factors can profoundly influence gene expression and, in turn, influence resistance or susceptibility to disease. Epigenetic drugs, such as histone deacetylase (HDAC) inhibitors, are finding their way into clinical practice, although their exact mechanisms of action are unclear. To identify mechanisms associated with HDAC inhibition, we performed microarray analysis on brain and muscle samples treated with the HDAC1/3-targeting inhibitor, HDACi 4b. Pathways analyses of microarray datasets implicate DNA methylation as significantly associated with HDAC inhibition. Further assessment of DNA methylation changes elicited by HDACi 4b in human fibroblasts from normal controls and patients with Huntington's disease (HD) using the Infinium HumanMethylation450 BeadChip revealed a limited, but overlapping, subset of methylated CpG sites that were altered by HDAC inhibition in both normal and HD cells. Among the altered loci of Y chromosome-linked genes, KDM5D, which encodes Lys (K)-specific demethylase 5D, showed increased methylation at several CpG sites in both normal and HD cells, as well as in DNA isolated from sperm from drug-treated male mice. Further, we demonstrate that first filial generation (F1) offspring from drug-treated male HD transgenic mice show significantly improved HD disease phenotypes compared with F1 offspring from vehicle-treated male HD transgenic mice, in association with increased Kdm5d expression, and decreased histone H3 Lys4 (K4) (H3K4) methylation in the CNS of male offspring. Additionally, we show that overexpression of Kdm5d in mutant HD striatal cells significantly improves metabolic deficits. These findings indicate that HDAC inhibitors can elicit transgenerational effects, via cross-talk between different epigenetic mechanisms, to have an impact on disease phenotypes in a beneficial manner. PMID:25535382

Jia, Haiqun; Morris, Charles D; Williams, Roy M; Loring, Jeanne F; Thomas, Elizabeth A

2015-01-01

154

Pressure Overload-Induced Cardiac Hypertrophy Response Requires Janus Kinase 2-Histone Deacetylase 2 Signaling  

PubMed Central

Pressure overload induces cardiac hypertrophy through activation of Janus kinase 2 (Jak2), however, the underlying mechanisms remain largely unknown. In the current study, we tested whether histone deacetylase 2 (HDAC2) was involved in the process. We found that angiotensin II (Ang-II)-induced re-expression of fetal genes (Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP)) in cultured cardiomyocytes was prevented by the Jak2 inhibitor AG-490 and HDAC2 inhibitor Trichostatin-A (TSA), or by Jak2/HDAC2 siRNA knockdown. On the other hand, myocardial cells with Jak2 or HDAC2 over-expression were hyper-sensitive to Ang-II. In vivo, pressure overload by transverse aorta binding (AB) induced a significant cardiac hypertrophic response as well as re-expression of ANP and BNP in mice heart, which were markedly reduced by AG-490 and TSA. Significantly, AG-490, the Jak2 inhibitor, largely suppressed pressure overload-/Ang-II-induced HDAC2 nuclear exportation in vivo and in vitro. Meanwhile, TSA or HDAC2 siRNA knockdown reduced Ang-II-induced ANP/BNP expression in Jak2 over-expressed H9c2 cardiomyocytes. Together, these results suggest that HDAC2 might be a downstream effector of Jak2 to mediate cardiac hypertrophic response by pressure overload or Ang-II. PMID:25380525

Ying, Huang; Xu, Mao-Chun; Tan, Jing-Hua; Shen, Jing-Hua; Wang, Hao; Zhang, Dai-Fu

2014-01-01

155

Pressure overload-induced cardiac hypertrophy response requires janus kinase 2-histone deacetylase 2 signaling.  

PubMed

Pressure overload induces cardiac hypertrophy through activation of Janus kinase 2 (Jak2), however, the underlying mechanisms remain largely unknown. In the current study, we tested whether histone deacetylase 2 (HDAC2) was involved in the process. We found that angiotensin II (Ang-II)-induced re-expression of fetal genes (Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP)) in cultured cardiomyocytes was prevented by the Jak2 inhibitor AG-490 and HDAC2 inhibitor Trichostatin-A (TSA), or by Jak2/HDAC2 siRNA knockdown. On the other hand, myocardial cells with Jak2 or HDAC2 over-expression were hyper-sensitive to Ang-II. In vivo, pressure overload by transverse aorta binding (AB) induced a significant cardiac hypertrophic response as well as re-expression of ANP and BNP in mice heart, which were markedly reduced by AG-490 and TSA. Significantly, AG-490, the Jak2 inhibitor, largely suppressed pressure overload-/Ang-II-induced HDAC2 nuclear exportation in vivo and in vitro. Meanwhile, TSA or HDAC2 siRNA knockdown reduced Ang-II-induced ANP/BNP expression in Jak2 over-expressed H9c2 cardiomyocytes. Together, these results suggest that HDAC2 might be a downstream effector of Jak2 to mediate cardiac hypertrophic response by pressure overload or Ang-II. PMID:25380525

Ying, Huang; Xu, Mao-Chun; Tan, Jing-Hua; Shen, Jing-Hua; Wang, Hao; Zhang, Dai-Fu

2014-01-01

156

Radionuclide Labeling and Evaluation of Candidate Radioligands for PET Imaging of Histone Deacetylase in the Brain  

PubMed Central

Histone deacetylases (HDACs) regulate gene expression by inducing conformational changes in chromatin. Ever since the discovery of a naturally occurring HDAC inhibitor, trichostatin A (TSA) stimulated the recent development of suberoylanilide (SAHA, Zolinza®), HDAC has become an important molecular target for drug development. This has created the need to develop specific in vivo radioligands to study epigenetic regulation and HDAC engagement for drug development for diseases including cancer and psychiatric disorders. 6-([18F]Fluoroacetamido)-1-hexanoicanilide ([18F]FAHA) was recently developed as a HDAC substrate and shows moderate blood-brain barrier (BBB) permeability and specific signal (by metabolic trapping/or deacetylation) but rapid metabolism. Here, we report the radiosynthesis of two carbon-11 labeled candidate radiotracers (substrate- and inhibitor-based radioligand) for HDAC and their evaluation in non-human primate brain. PET studies showed very low brain uptake and rapid metabolism of both labeled compounds but revealed a surprising enhancement of brain penetration by F for H substitution when comparing one of these to [18F]FAHA. Further structural refinement is needed for the development of brain-penetrant, metabolically stable HDAC radiotracers and to understand the role of fluorine substitution on brain penetration. PMID:24210501

Seo, Young Jun; Muench, Lisa; Reid, Alicia; Chen, Jinzhu; Kang, Yeona; Hooker, Jacob M.; Volkow, Nora D.; Fowler, Joanna S.; Kim, Sung Won

2013-01-01

157

Neural stem cell differentiation is dictated by distinct actions of nuclear receptor corepressors and histone deacetylases.  

PubMed

Signaling factors including retinoic acid (RA) and thyroid hormone (T3) promote neuronal, oligodendrocyte, and astrocyte differentiation of cortical neural stem cells (NSCs). However, the functional specificity of transcriptional repressor checkpoints controlling these differentiation programs remains unclear. Here, we show by genome-wide analysis that histone deacetylase (HDAC)2 and HDAC3 show overlapping and distinct promoter occupancy at neuronal and oligodendrocyte-related genes in NSCs. The absence of HDAC3, but not HDAC2, initiated a neuronal differentiation pathway in NSCs. The ablation of the corepressor NCOR or HDAC2, in conjunction with T3 treatment, resulted in increased expression of oligodendrocyte genes, revealing a direct HDAC2-mediated repression of Sox8 and Sox10 expression. Interestingly, Sox10 was required also for maintaining the more differentiated state by repression of stem cell programming factors such as Sox2 and Sox9. Distinct and nonredundant actions of NCORs and HDACs are thus critical for control of lineage progression and differentiation programs in neural progenitors. PMID:25241747

Castelo-Branco, Gonçalo; Lilja, Tobias; Wallenborg, Karolina; Falcão, Ana M; Marques, Sueli C; Gracias, Aileen; Solum, Derek; Paap, Ricardo; Walfridsson, Julian; Teixeira, Ana I; Rosenfeld, Michael G; Jepsen, Kristen; Hermanson, Ola

2014-09-01

158

Chemical probes identify a role for histone deacetylase 3 in Friedreich’s ataxia gene silencing  

PubMed Central

SUMMARY We recently identified a novel class of pimelic diphenylamide histone deacetylase (HDAC) inhibitors that show promise as therapeutics in the neurodegenerative diseases Friedreich’s ataxia (FRDA) and Huntington’s disease. Here we describe chemical approaches to identify the HDAC enzyme target of these inhibitors. Incubation of a trifunctional activity-based probe with a panel of class I and class II recombinant HDAC enzymes, followed by click chemistry addition of a fluorescent dye and gel electrophoresis, identifies HDAC3 as a unique high-affinity target of the probe. Photoaffinity labeling in a nuclear extract prepared from human lymphoblasts with the trifunctional probe, followed by biotin addition through click chemistry, streptavidin enrichment and western blotting also identifies HDAC3 as the preferred cellular target of the inhibitor. Additional inhibitors with different HDAC specificity profiles were synthesized and results from transcription experiments in FRDA cells point to a unique role for HDAC3 in gene silencing in Friedreich’s ataxia. PMID:19778726

Xu, Chunping; Soragni, Elisabetta; Chou, C. James; Herman, David; Plasterer, Heather L.; Rusche, James R.; Gottesfeld, Joel M.

2010-01-01

159

Functional dissection of lysine deacetylases reveals that HDAC1 and p300 regulate AMPK.  

PubMed

First identified as histone-modifying proteins, lysine acetyltransferases (KATs) and deacetylases (KDACs) antagonize each other through modification of the side chains of lysine residues in histone proteins. Acetylation of many non-histone proteins involved in chromatin, metabolism or cytoskeleton regulation were further identified in eukaryotic organisms, but the corresponding enzymes and substrate-specific functions of the modifications are unclear. Moreover, mechanisms underlying functional specificity of individual KDACs remain enigmatic, and the substrate spectra of each KDAC lack comprehensive definition. Here we dissect the functional specificity of 12 critical human KDACs using a genome-wide synthetic lethality screen in cultured human cells. The genetic interaction profiles revealed enzyme-substrate relationships between individual KDACs and many important substrates governing a wide array of biological processes including metabolism, development and cell cycle progression. We further confirmed that acetylation and deacetylation of the catalytic subunit of the adenosine monophosphate-activated protein kinase (AMPK), a critical cellular energy-sensing protein kinase complex, is controlled by the opposing catalytic activities of HDAC1 and p300. Deacetylation of AMPK enhances physical interaction with the upstream kinase LKB1, leading to AMPK phosphorylation and activation, and resulting in lipid breakdown in human liver cells. These findings provide new insights into previously underappreciated metabolic regulatory roles of HDAC1 in coordinating nutrient availability and cellular responses upstream of AMPK, and demonstrate the importance of high-throughput genetic interaction profiling to elucidate functional specificity and critical substrates of individual human KDACs potentially valuable for therapeutic applications. PMID:22318606

Lin, Yu-yi; Kiihl, Samara; Suhail, Yasir; Liu, Shang-Yun; Chou, Yi-hsuan; Kuang, Zheng; Lu, Jin-ying; Khor, Chin Ni; Lin, Chi-Long; Bader, Joel S; Irizarry, Rafael; Boeke, Jef D

2012-02-01

160

Holocarboxylase synthetase interacts physically with nuclear receptor co-repressor, histone deacetylase 1 and a novel splicing variant of histone deacetylase 1 to repress repeats.  

PubMed

HLCS (holocarboxylase synthetase) is a nuclear protein that catalyses the binding of biotin to distinct lysine residues in chromatin proteins. HLCS-dependent epigenetic marks are over-represented in repressed genomic loci, particularly in repeats. Evidence is mounting that HLCS is a member of a multi-protein gene repression complex, which determines its localization in chromatin. In the present study we tested the hypothesis that HLCS interacts physically with N-CoR (nuclear receptor co-repressor) and HDAC1 (histone deacetylase 1), thereby contributing toward the removal of H3K9ac (Lys?-acetylated histone H3) gene activation marks and the repression of repeats. Physical interactions between HLCS and N-CoR, HDAC1 and a novel splicing variant of HDAC1 were confirmed by co-immunoprecipitation, limited proteolysis and split luciferase complementation assays. When HLCS was overexpressed, the abundance of H3K9ac marks decreased by 50% and 68% in LTRs (long terminal repeats) 15 and 22 respectively in HEK (human embryonic kidney)-293 cells compared with the controls. This loss of H3K9ac marks was linked with an 83% decrease in mRNA coding for LTRs. Similar patterns were seen in pericentromeric alpha satellite repeats in chromosomes 1 and 4. We conclude that interactions of HLCS with N-CoR and HDACs contribute towards the transcriptional repression of repeats, presumably increasing genome stability. PMID:24840043

Liu, Dandan; Zempleni, Janos

2014-08-01

161

Histone deacetylase inhibitors induce apoptosis in both Type I and Type II endometrial cancer cells  

PubMed Central

Objective To characterize the molecular pathways involved in apoptosis following administration of histone deacetylase inhibitors to Type I and II endometrial cancer cells. Methods Ark2, Ishikawa, and AN3 cell lines representing both Type I and II endometrial cancers were treated with various concentrations of oxamflatin and HDAC inhibitor-1. Cell apoptosis was determined by flow cytometry, nuclear staining, Western blotting, and mitochondrial membrane potential assays. Results Compared to controls, there was a 95% reduction in the growth of Ark2 cells following administration of histone deacetylase inhibitors and this response was dose-dependent. These agents also caused profound morphologic changes and loss of mitochondrial membrane potentials consistent with the induction of apoptosis. Cleavage of PARP, caspase-9, and caspase-8 was detected, confirming the activation of apoptotic cascades in endometrial carcinoma cells. This effect was present in both serous and endometrioid cell types. Conclusion Our results suggest that oxamflatin and HDAC inhibitor-1 have potent cytotoxicity in endometrial cancer cells by inducing cell apoptosis. Histone deacetylase inhibitors are promising agents for the treatment of both Type I and II endometrial carcinoma. PMID:17303224

Jiang, Shujuan; Dowdy, Sean C.; Meng, Xue W.; Wang, Zhaoyu; Jones, Monica B.; Podratz, Karl C.; Jiang, Shi-Wen

2012-01-01

162

Decreased histone deacetylase 2 impairs Nrf2 activation by oxidative stress  

SciTech Connect

Research highlights: {yields} Nrf2 anti-oxidant function is impaired when HDAC activity is inhibited. {yields} HDAC inhibition decreases Nrf2 protein stability. {yields} HDAC2 is involved in reduced Nrf2 stability and both correlate in COPD samples. {yields} HDAC inhibition increases Nrf2 acetylation. -- Abstract: Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a crucial role in cellular defence against oxidative stress by inducing the expression of multiple anti-oxidant genes. However, where high levels of oxidative stress are observed, such as chronic obstructive pulmonary disease (COPD), Nrf2 activity is reduced, although the molecular mechanism for this defect is uncertain. Here, we show that down-regulation of histone deacetylase (HDAC) 2 causes Nrf2 instability, resulting in reduced anti-oxidant gene expression and increase sensitivity to oxidative stress. Although Nrf2 protein was clearly stabilized after hydrogen peroxide (H{sub 2}O{sub 2}) stimulation in a bronchial epithelial cell line (BEAS2B), Nrf2 stability was decreased and Nrf2 acetylation increased in the presence of an HDAC inhibitor, trichostatin A (TSA). TSA also reduced Nrf2-regulated heme-oxygenase-1 (HO-1) expression in these cells, and this was confirmed in acute cigarette-smoke exposed mice in vivo. HDAC2 knock-down by RNA interference resulted in reduced H{sub 2}O{sub 2}-induced Nrf2 protein stability and activity in BEAS2B cells, whereas HDAC1 knockdown had no effect. Furthermore, monocyte-derived macrophages obtained from healthy volunteers (non-smokers and smokers) and COPD patients showed a significant correlation between HDAC2 expression and Nrf2 expression (r = 0.92, p < 0.0001). Thus, reduced HDAC2 activity in COPD may account for increased Nrf2 acetylation, reduced Nrf2 stability and impaired anti oxidant defences.

Mercado, Nicolas [Airway Disease Section, National Heart and Lung Institute, Imperial College, London SW3 6LY (United Kingdom)] [Airway Disease Section, National Heart and Lung Institute, Imperial College, London SW3 6LY (United Kingdom); Thimmulappa, Rajesh [Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (United States)] [Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (United States); Thomas, Catherine M.R.; Fenwick, Peter S.; Chana, Kirandeep K.; Donnelly, Louise E. [Airway Disease Section, National Heart and Lung Institute, Imperial College, London SW3 6LY (United Kingdom)] [Airway Disease Section, National Heart and Lung Institute, Imperial College, London SW3 6LY (United Kingdom); Biswal, Shyam [Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (United States)] [Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (United States); Ito, Kazuhiro [Airway Disease Section, National Heart and Lung Institute, Imperial College, London SW3 6LY (United Kingdom)] [Airway Disease Section, National Heart and Lung Institute, Imperial College, London SW3 6LY (United Kingdom); Barnes, Peter J., E-mail: p.j.barnes@imperial.ac.uk [Airway Disease Section, National Heart and Lung Institute, Imperial College, London SW3 6LY (United Kingdom)

2011-03-11

163

Trend of histone deacetylase inhibitors in cancer therapy: isoform selectivity or multitargeted strategy.  

PubMed

Pharmacological inhibition of histone deacetylases (HDACs) has been successfully applied in the treatment of a wide range of disorders, including Parkinson's disease, infection, cardiac diseases, inflammation, and especially cancer. HDAC inhibitors (HDACIs) have been proved to be effective antitumor agents by various stages of investigation. At present, there are two opposite focuses of HDACI design in the cancer therapy, highly selective inhibitor strategy and dual- or multitargeted inhibitors. The former method, which is supposed to elucidate the function of individual HDAC and provide candidate inhibitors with fewer side effects, has been widely accepted by the inhibitor developer. The latter approach, though less practiced, has promising potential for the antitumor therapy based on HDACIs. Effective HDACIs, some of which are in clinic anticancer research, have been developed by both methods. In order to gain insight into HDACI design, the strategies and achievements of the two diverse methods are reviewed. PMID:24782318

Zhang, Lei; Han, Yantao; Jiang, Qixiao; Wang, Chunbo; Chen, Xuehong; Li, Xiaoguang; Xu, Fuming; Jiang, Yuqi; Wang, Qiang; Xu, Wenfang

2015-01-01

164

Tropolones As Lead-Like Natural Products: The Development of Potent and Selective Histone Deacetylase Inhibitors  

PubMed Central

Natural products have long been recognized as a rich source of potent therapeutics but further development is often limited by high structural complexity and high molecular weight. In contrast, at the core of the thujaplicins is a lead-like tropolone scaffold characterized by relatively low molecular weight, ample sites for diversification, and metal-binding functionality poised for targeting a range of metalloenzyme drug targets. Here, we describe the development of this underutilized scaffold for the discovery of tropolone derivatives that function as isozyme-selective inhibitors of the validated anticancer drug target, histone deacetylase (HDAC). Several monosubstituted tropolones display remarkable levels of selectivity for HDAC2 and potently inhibit the growth of T-cell lymphocyte cell lines. The tropolones represent a new chemotype of isozyme-selective HDAC inhibitors. PMID:24900743

2013-01-01

165

Histone deacetylase inhibition regulates inflammation and enhances Tregs after allogeneic hematopoietic cell transplantation in humans  

PubMed Central

We examined immunological responses in patients receiving histone deacetylase (HDAC) inhibition (vorinostat) for graft-versus-host disease prophylaxis after allogeneic hematopoietic cell transplant. Vorinostat treatment increased histone acetylation in peripheral blood mononuclear cells (PBMCs) from treated patients, confirming target HDAC inhibition. HDAC inhibition reduced proinflammatory cytokine levels in plasma and from PBMCs and decreased ex vivo responses of PBMCs to proinflammatory TLR-4 stimuli, but did not alter the number or response of conventional T cells to nonspecific stimuli. However, the numbers of regulatory T cells (Tregs) were increased, which revealed greater demethylation of the Foxp3 T regulatory-specific demethylation region. Vorinostat-treated patients showed increased expression of CD45RA and CD31 on Tregs, and these Tregs demonstrated greater suppression on a per cell basis. Consistent with preclinical findings, HDAC inhibition also increased signal transducer and activator of transcription 3 acetylation and induced indoleamine-2,3-dioxygenase. Our data demonstrate that HDAC inhibition reduces inflammatory responses of PBMC but enhances Tregs after allo-HCT. PMID:25428224

Choi, Sung Won; Gatza, Erin; Hou, Guoqing; Sun, Yaping; Whitfield, Joel; Song, Yeohan; Oravecz-Wilson, Katherine; Tawara, Isao; Dinarello, Charles A.

2015-01-01

166

The Histone Deacetylase Inhibitor Trichostatin A Promotes Totipotency in the Male Gametophyte[W  

PubMed Central

The haploid male gametophyte, the pollen grain, is a terminally differentiated structure whose function ends at fertilization. Plant breeding and propagation widely use haploid embryo production from in vitro–cultured male gametophytes, but this technique remains poorly understood at the mechanistic level. Here, we show that histone deacetylases (HDACs) regulate the switch to haploid embryogenesis. Blocking HDAC activity with trichostatin A (TSA) in cultured male gametophytes of Brassica napus leads to a large increase in the proportion of cells that switch from pollen to embryogenic growth. Embryogenic growth is enhanced by, but not dependent on, the high-temperature stress that is normally used to induce haploid embryogenesis in B. napus. The male gametophyte of Arabidopsis thaliana, which is recalcitrant to haploid embryo development in culture, also forms embryogenic cell clusters after TSA treatment. Genetic analysis suggests that the HDAC protein HDA17 plays a role in this process. TSA treatment of male gametophytes is associated with the hyperacetylation of histones H3 and H4. We propose that the totipotency of the male gametophyte is kept in check by an HDAC-dependent mechanism and that the stress treatments used to induce haploid embryo development in culture impinge on this HDAC-dependent pathway. PMID:24464291

Li, Hui; Soriano, Mercedes; Cordewener, Jan; Muiño, Jose M.; Riksen, Tjitske; Fukuoka, Hiroyuki; Angenent, Gerco C.; Boutilier, Kim

2014-01-01

167

A novel histone deacetylase inhibitor Chidamide induces apoptosis of human colon cancer cells  

SciTech Connect

Many studies have demonstrated that histone deacetylase (HDAC) inhibitors induce various tumor cells to undergo apoptosis, and such inhibitors have been used in different clinical trials against different human cancers. In this study, we designed and synthesized a novel HDAC inhibitor, Chidamide. We showed that Chidamide was able to increase the acetylation levels of histone H3 and to inhibit the PI3K/Akt and MAPK/Ras signaling pathways, which resulted in arresting colon cancer cells at the G1 phase of the cell cycle and promoting apoptosis. As a result, the proliferation of colon cancer cells was suppressed in vitro. Our data support the potential application of Chidamide as an anticancer agent in treating colon cancer. Future studies are needed to demonstrate its in vivo efficacy.

Liu, Lin [Department of Oncology, Zhong-Da Hospital of Southeast University, Nanjing 210009, Jiangsu (China)] [Department of Oncology, Zhong-Da Hospital of Southeast University, Nanjing 210009, Jiangsu (China); Chen, Baoan, E-mail: wenyu811@126.com [Department of Oncology, Zhong-Da Hospital of Southeast University, Nanjing 210009, Jiangsu (China)] [Department of Oncology, Zhong-Da Hospital of Southeast University, Nanjing 210009, Jiangsu (China); Qin, Shukui [Chinese PLA Cancer Center, The 81st PLA Hospital, Nanjing 210002, Jiangsu (China)] [Chinese PLA Cancer Center, The 81st PLA Hospital, Nanjing 210002, Jiangsu (China); Li, Suyi; He, Xiangming [Department of Oncology, Zhong-Da Hospital of Southeast University, Nanjing 210009, Jiangsu (China)] [Department of Oncology, Zhong-Da Hospital of Southeast University, Nanjing 210009, Jiangsu (China); Qiu, Shaomin; Zhao, Wei; Zhao, Hong [Department of Internal Medicine, Nanjing Municipal Cancer Hospital, Nanjing 210003, Jiangsu (China)] [Department of Internal Medicine, Nanjing Municipal Cancer Hospital, Nanjing 210003, Jiangsu (China)

2010-02-05

168

Loss of histone deacetylase 4 causes segregation defects during mitosis of p53-deficient human tumor cells.  

PubMed

We investigated the role of histone deacetylase 4 (HDAC4) using RNA interference (RNAi) and knockout cells to specifically address its role in cell cycle progression in tumor and normal cells. Ablation of HDAC4 led to growth inhibition in human tumor cells but not to detectable effects in normal human dermal fibroblasts (NHDF) or myelopoietic progenitors. HDAC4-/+ or HDAC4-/- murine embryonic fibroblasts showed no detectable growth defects. On the other hand, HDAC4 RNAi in HeLa cells produced mitotic arrest followed by caspase-dependent apoptosis. Mitotically arrested cells showed chromosome segregation defects. Even though the growth of both p53-wild-type and p53-null tumor cells were affected by HDAC4 ablation, segregation defects were observed only in p53-null cells. HDAC4 associates with the PP2A-B56 regulatory subunit, which is known to be involved in chromosome segregation, and RNAi of either the structural subunit A or the regulatory subunit B56 of PP2A also caused chromosome segregation defects. We conclude that HDAC4 is required for cell cycle progression of tumor cells by multiple mechanisms, one of which seems to be specific to p53-deficient cells through chromosome segregation defects. On the contrary, HDAC4 is not required for the progression of NHDF. We therefore suggest that systemic selective interference with the expression or function of HDAC4 is expected to have a significant therapeutic window, in particular, for p53-deficient tumors. PMID:19622775

Cadot, Bruno; Brunetti, Mirko; Coppari, Sabina; Fedeli, Silvia; de Rinaldis, Emanuele; Dello Russo, Claudio; Gallinari, Paola; De Francesco, Raffaele; Steinkühler, Christian; Filocamo, Gessica

2009-08-01

169

Histone Deacetylase Inhibitors Improve the Replication of Oncolytic Herpes Simplex Virus in Breast Cancer Cells  

PubMed Central

New therapies are needed for metastatic breast cancer patients. Oncolytic herpes simplex virus (oHSV) is an exciting therapy being developed for use against aggressive tumors and established metastases. Although oHSV have been demonstrated safe in clinical trials, a lack of sufficient potency has slowed the clinical application of this approach. We utilized histone deacetylase (HDAC) inhibitors, which have been noted to impair the innate antiviral response and improve gene transcription from viral vectors, to enhance the replication of oHSV in breast cancer cells. A panel of chemically diverse HDAC inhibitors were tested at three different doses (<, ?=?, and >LD50) for their ability to modulate the replication of oHSV in breast cancer cells. Several of the tested HDAC inhibitors enhanced oHSV replication at low multiplicity of infection (MOI) following pre-treatment of the metastatic breast cancer cell line MDA-MB-231 and the oHSV-resistant cell line 4T1, but not in the normal breast epithelial cell line MCF10A. Inhibitors of class I HDACs, including pan-selective compounds, were more effective for increasing oHSV replication compared to inhibitors that selectively target class II HDACs. These studies demonstrate that select HDAC inhibitors increase oHSV replication in breast cancer cells and provides support for pre-clinical evaluation of this combination strategy. PMID:24651853

Cody, James J.; Markert, James M.; Hurst, Douglas R.

2014-01-01

170

Zinc chelation with hydroxamate in histone deacetylases modulated by water access to the linker binding channel.  

PubMed

It is of significant biological interest and medical importance to develop class- and isoform-selective histone deacetylase (HDAC) modulators. The impact of the linker component on HDAC inhibition specificity has been revealed but is not understood. Using Born-Oppenheimer ab initio QM/MM MD simulations, a state-of-the-art approach to simulating metallo-enzymes, we have found that the hydroxamic acid remains to be protonated upon its binding to HDAC8, and thus disproved the mechanistic hypothesis that the distinct zinc-hydroxamate chelation modes between two HDAC subclasses come from different protonation states of the hydroxamic acid. Instead, our simulations suggest a novel mechanism in which the chelation mode of hydroxamate with the zinc ion in HDACs is modulated by water access to the linker binding channel. This new insight into the interplay between the linker binding and the zinc chelation emphasizes its importance and gives guidance regarding linker design for the development of new class-IIa-specific HDAC inhibitors. PMID:21456530

Wu, Ruibo; Lu, Zhenyu; Cao, Zexing; Zhang, Yingkai

2011-04-27

171

Structures of metal-substituted human histone deacetylase 8 provide mechanistic inferences on biological function .  

PubMed

The metal-dependent histone deacetylases (HDACs) adopt an alpha/beta protein fold first identified in rat liver arginase. Despite insignificant overall amino acid sequence identity, these enzymes share a strictly conserved metal binding site with divergent metal specificity and stoichiometry. HDAC8, originally thought to be a Zn(2+)-metallohydrolase, exhibits increased activity with Co(2+) and Fe(2+) cofactors based on k(cat)/K(M) (Gantt, S. L., Gattis, S. G., and Fierke, C. A. (2006) Biochemistry 45, 6170-6178). Here, we report the first X-ray crystal structures of metallo-substituted HDAC8, Co(2+)-HDAC8, D101L Co(2+)-HDAC8, D101L Mn(2+)-HDAC8, and D101L Fe(2+)-HDAC8, each complexed with the inhibitor M344. Metal content of protein samples in solution is confirmed by inductively coupled plasma mass spectrometry. For the crystalline enzymes, peaks in Bijvoet difference Fourier maps calculated from X-ray diffraction data collected near the respective elemental absorption edges confirm metal substitution. Additional solution studies confirm incorporation of Cu(2+); Fe(3+) and Ni(2+) do not bind under conditions tested. The metal dependence of the substrate K(M) values and the K(i) values of hydroxamate inhibitors that chelate the active site metal are consistent with substrate-metal coordination in the precatalytic Michaelis complex that enhances catalysis. Additionally, although HDAC8 binds Zn(2+) nearly 10(6)-fold more tightly than Fe(2+), the affinities for both metal ions are comparable to the readily exchangeable metal concentrations estimated in living cells, suggesting that HDAC8 could bind either or both Fe(2+) or Zn(2+) in vivo. PMID:20545365

Dowling, Daniel P; Gattis, Samuel G; Fierke, Carol A; Christianson, David W

2010-06-22

172

Structures of Metal-Substituted Human Histone Deacetylase 8 Provide Mechanistic Inferences on Biological Function  

SciTech Connect

The metal-dependent histone deacetylases (HDACs) adopt an {alpha}/{beta} protein fold first identified in rat liver arginase. Despite insignificant overall amino acid sequence identity, these enzymes share a strictly conserved metal binding site with divergent metal specificity and stoichiometry. HDAC8, originally thought to be a Zn{sup 2+}-metallohydrolase, exhibits increased activity with Co{sup 2+} and Fe{sup 2+} cofactors based on k{sub cat}/K{sub M} (Gantt, S. L., Gattis, S. G., and Fierke, C. A. (2006) Biochemistry 45, 6170-6178). Here, we report the first X-ray crystal structures of metallo-substituted HDAC8, Co{sup 2+}-HDAC8, D101L Co{sup 2+}-HDAC8, D101L Mn{sup 2+}-HDAC8, and D101L Fe{sup 2+}-HDAC8, each complexed with the inhibitor M344. Metal content of protein samples in solution is confirmed by inductively coupled plasma mass spectrometry. For the crystalline enzymes, peaks in Bijvoet difference Fourier maps calculated from X-ray diffraction data collected near the respective elemental absorption edges confirm metal substitution. Additional solution studies confirm incorporation of Cu{sup 2+}; Fe{sup 3+} and Ni{sup 2+} do not bind under conditions tested. The metal dependence of the substrate K{sub M} values and the K{sub i} values of hydroxamate inhibitors that chelate the active site metal are consistent with substrate-metal coordination in the precatalytic Michaelis complex that enhances catalysis. Additionally, although HDAC8 binds Zn{sup 2+} nearly 106-fold more tightly than Fe{sup 2+}, the affinities for both metal ions are comparable to the readily exchangeable metal concentrations estimated in living cells, suggesting that HDAC8 could bind either or both Fe{sup 2+} or Zn{sup 2+} in vivo.

Dowling, Daniel P.; Gattis, Samuel G.; Fierke, Carol A.; Christianson, David W. (Michigan); (UPENN)

2010-08-23

173

Sin3a-associated Hdac1 and Hdac2 are essential for hematopoietic stem cell homeostasis and contribute differentially to hematopoiesis.  

PubMed

Class I histone deacetylases are critical regulators of gene transcription by erasing lysine acetylation. Targeting histone deacetylases using relative non-specific small molecule inhibitors is of major interest in the treatment of cancer, neurological disorders and acquired immune deficiency syndrome. Harnessing the therapeutic potential of histone deacetylase inhibitors requires full knowledge of individual histone deacetylases in vivo. As hematologic malignancies show increased sensitivity towards histone deacetylase inhibitors we targeted deletion of class I Hdac1 and Hdac2 to hematopoietic cell lineages. Here, we show that Hdac1 and Hdac2 together control hematopoietic stem cell homeostasis, in a cell-autonomous fashion. Simultaneous loss of Hdac1 and Hdac2 resulted in loss of hematopoietic stem cells and consequently bone marrow failure. Bone-marrow-specific deletion of Sin3a, a major Hdac1/2 co-repressor, phenocopied loss of Hdac1 and Hdac2 indicating that Sin3a-associated HDAC1/2-activity is essential for hematopoietic stem cell homeostasis. Although Hdac1 and Hdac2 show compensatory and overlapping functions in hematopoiesis, mice expressing mono-allelic Hdac1 or Hdac2 revealed that Hdac1 and Hdac2 contribute differently to the development of specific hematopoietic lineages. PMID:24763403

Heideman, Marinus R; Lancini, Cesare; Proost, Natalie; Yanover, Eva; Jacobs, Heinz; Dannenberg, Jan-Hermen

2014-08-01

174

Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory.  

PubMed

FTY720 (fingolimod), an FDA-approved drug for treatment of multiple sclerosis, has beneficial effects in the CNS that are not yet well understood, independent of its effects on immune cell trafficking. We show that FTY720 enters the nucleus, where it is phosphorylated by sphingosine kinase 2 (SphK2), and that nuclear FTY720-P binds and inhibits class I histone deacetylases (HDACs), enhancing specific histone acetylations. FTY720 is also phosphorylated in mice and accumulates in the brain, including the hippocampus, inhibits HDACs and enhances histone acetylation and gene expression programs associated with memory and learning, and rescues memory deficits independently of its immunosuppressive actions. Sphk2(-/-) mice have lower levels of hippocampal sphingosine-1-phosphate, an endogenous HDAC inhibitor, and reduced histone acetylation, and display deficits in spatial memory and impaired contextual fear extinction. Thus, sphingosine-1-phosphate and SphK2 play specific roles in memory functions and FTY720 may be a useful adjuvant therapy to facilitate extinction of aversive memories. PMID:24859201

Hait, Nitai C; Wise, Laura E; Allegood, Jeremy C; O'Brien, Megan; Avni, Dorit; Reeves, Thomas M; Knapp, Pamela E; Lu, Junyan; Luo, Cheng; Miles, Michael F; Milstien, Sheldon; Lichtman, Aron H; Spiegel, Sarah

2014-07-01

175

Acetylation of core histones in response to HDAC inhibitors is diminished in mitotic HeLa cells  

PubMed Central

Histone acetylation is a key modification that regulates chromatin accessibility. Here we show that treatment with butyrate or other histone deacetylase (HDAC) inhibitors does not induce histone hyperacetylation in metaphase-arrested HeLa cells. When compared to similarly treated interphase cells, acetylation levels are significantly decreased in all four core histones and at all individual sites examined. However, the extent of the decrease varies, ranging from only slight reduction at H3K23 and H4K12 to no acetylation at H3K27 and barely detectable acetylation at H4K16. Our results show that the bulk effect is not due to increased or butyrate-insensitive HDAC activity, though these factors may play a role with some individual sites. We conclude that the lack of histone acetylation during mitosis is primarily due to changes in histone acetyltransferases (HATs) or changes in chromatin. The effects of protein phosphatase inhibitors on histone acetylation in cell lysates suggest that the reduced ability of histones to become acetylated in mitotic cells depends on protein phosphorylation. PMID:20452346

Patzlaff, Jason S.; Terrenoire, Edith; Turner, Bryan M.; Earnshaw, William C.; Paulson, James R.

2010-01-01

176

Pure curcumin increases the expression of SOCS1 and SOCS3 in myeloproliferative neoplasms through suppressing class I histone deacetylases.  

PubMed

Suppressors of cytokine signaling, SOCS1 and SOCS3, are important negative regulators of Janus kinase 2/signal transducers and activators of transcription signaling, which is constitutively activated in myeloproliferative neoplasms (MPNs) and leukemia. Curcumin has been shown to possess anticancer activity through different mechanisms. However, whether curcumin can regulate the expression of SOCS1 and SOCS3 is still unknown. Here, we found that curcumin elevated the expression of SOCS1 and SOCS3 via triggering acetylation of histone in the regions of SOCS1 and SOCS3 promoter in K562 and HEL cells. As a novel histone deacetylases (HDACs) inhibitor, curcumin inhibited HDAC enzyme activities and decreased the levels of HDAC1, 3 and 8 but not HDAC2. Knockdown of HDAC8 by small interfering RNA markedly elevated the expression of SOCS1 and SOCS3. Moreover, ectopic expression of HDAC8 decreased the levels of SOCS1 and SOCS3. Thus, HDAC8 plays an important role in the modulation of SOCS1 and SOCS3 by curcumin. Also, trichostatin A (TSA), an inhibitor of HDACs, increased the levels of SOCS1 and SOCS3. Furthermore, curcumin increased the transcript levels of SOCS1 and SOCS3 and significantly inhibited the clonogenic activity of hematopoietic progenitors from patients with MPNs. Finally, curcumin markedly inhibited HDAC activities and decreased HDAC8 levels in primary MPN cells. Taken together, our data uncover a regulatory mechanism of SOCS1 and SOCS3 through inhibition of HDAC activity (especially HDAC8) by curcumin. Thus, being a relative non-toxic agent, curcumin may offer a therapeutic advantage in the clinical treatment for MPNs. PMID:23430957

Chen, Chi-qi; Yu, Kang; Yan, Qing-xian; Xing, Chong-yun; Chen, Yi; Yan, Zhuang; Shi, Yi-fen; Zhao, Ke-wen; Gao, Shen-meng

2013-07-01

177

Histone Deacetylases 6 and 9 and Sirtuin-1 Control Foxp3+ Regulatory T Cell Function Through Shared and Isotype-Specific Mechanisms  

PubMed Central

Therapeutic targeting of histone/protein deacetylase 6 (HDAC6), HDAC9, or the sirtuin-1 (Sirt1) augments the suppressive functions of regulatory T cells (Tregs) that contain the transcription factor Foxp3. However, it is unclear whether distinct mechanisms are involved or whether combined inhibition of these targets would be more beneficial. We compared the suppressive functions of Tregs from wild-type C57BL/6 mice with those from mice with either global (HDAC6?/?, HDAC9?/?, and HDAC6?/?HDAC9?/?), or conditional (fl-Sirt1/CD4-Cre or fl-Sirt1/Foxp3-Cre) HDAC deletion, as well as treatment with isoform-selective HDAC inhibitors. We found that the heat shock response was important for the improvement of Treg suppressive function mediated by HDAC6 inhibition, but not Sirt1 inhibition. Furthermore, although HDAC6, HDAC9, and Sirt1 all deacetylated Foxp3, each protein had diverse effects on transcription factors controlling Foxp3 gene expression. For example, loss of HDAC9 was associated with stabilization of the acetylation of signal transducer and activator of transcription 5 (STAT5) and of its transcriptional activity. Hence, targeting different HDACs increased Treg function by multiple and additive mechanisms, which indicates the therapeutic potential for combinations of HDAC inhibitors in the management of autoimmunity and organ transplantation. PMID:22715468

Beier, Ulf H.; Wang, Liqing; Han, Rongxiang; Akimova, Tatiana; Liu, Yujie; Hancock, Wayne W.

2013-01-01

178

Liposomes loaded with histone deacetylase inhibitors for breast cancer therapy.  

PubMed

Histone deacetylase (HDAC) inhibitors (HDACi) of the class I trichostatin A (TSA), CG1521 (CG), and PXD101 (PXD) were incorporated at a high rate (approximately 1mM) in liposomes made of egg phosphatidylcholine/cholesterol/distearoylphosphoethanolamine-polyethylenglycol(2000) (64:30:6). Physicochemical parameters (size, zeta potential, loading, stability, release kinetics) of these HDACi-loaded pegylated liposomes were optimized and their cytotoxicity (MTT test) was measured in MCF-7, T47-D, MDA-MB-231 and SkBr3 breast cancer cell lines. In MCF-7 cells, TSA and PXD were efficient inducers of proteasome-mediated estradiol receptor alpha degradation and they both affected estradiol-induced transcription (TSA>PXD) contrary to CG. Moreover, TSA most efficiently altered breast cancer cell viability as compared to the free drug, CG-liposomes being the weakest, while unloaded liposomes had nearly no cytotoxicity. Pegylated liposomes loaded with TSA or PXD remained stable in size, charge and biological activity for one month when stored at 4 degrees C. All HDACi-loaded liposomes released slowly the encapsulated drug in vitro, CG-loaded liposomes showed the slowest release kinetic. These formulations could improve the efficacy of HDACi not only in breast cancers but also in other solid tumors because most of these drugs are poor water soluble and unstable in vivo, and their administration remains a challenge. PMID:20603204

Urbinati, Giorgia; Marsaud, Véronique; Plassat, Vincent; Fattal, Elias; Lesieur, Sylviane; Renoir, Jack-Michel

2010-09-15

179

Histone deacetylase inhibitors equipped with estrogen receptor modulation activity.  

PubMed

We describe a set of novel histone deacetylase inhibitors (HDACi) equipped with either an antagonist or an agonist of the estrogen receptor (ER) to confer selective activity against breast cancers. These bifunctional compounds potently inhibit HDAC at nanomolar concentrations and either agonize or antagonize ER? and ER?. The ER antagonist activities of tamoxifen-HDACi conjugates (Tam-HDACi) are nearly identical to those of tamoxifen. Conversely, ethynyl-estradiol-HDACi conjugates (EED-HDACi) have attenuated ER agonist activities relative to the parent ethynyl-estradiol. In silico docking analysis provides structural basis for the trends of ER agonism/antagonism and ER subtype selectivity. Excitingly, lead Tam-HDACi conjugates show anticancer activity that is selectively more potent against MCF-7 (ER? positive breast cancer) compared to MDA-MB-231 (triple negative breast cancer), DU145 (prostate cancer), or Vero (noncancerous cell line). This dual-targeting approach illustrates the utility of designing small molecules with an emphasis on cell-type selectivity, not merely improved potency, working toward a higher therapeutic index at the earliest stages of drug development. PMID:23786452

Gryder, Berkley E; Rood, Michael K; Johnson, Kenyetta A; Patil, Vishal; Raftery, Eric D; Yao, Li-Pan D; Rice, Marcie; Azizi, Bahareh; Doyle, Donald F; Oyelere, Adegboyega K

2013-07-25

180

Histone Deacetylase Inhibitors Equipped with Estrogen Receptor Modulation Activity  

PubMed Central

We described a set of novel histone deacetylase inhibitors (HDACi) equipped with either an antagonist or an agonist of the estrogen receptor (ER) to confer selective activity against breast cancers. These bifunctional compounds potently inhibit HDAC at nanomolar concentrations, and either agonize or antagonize ER? and ER?. The ER antagonist activities of tamoxifen-HDACi conjugates (Tam-HDACi) are nearly identical to those of tamoxifen. Conversely, ethynyl-estradiol HDACi conjugates (EED-HDACi) have attenuated ER agonist activities relative to the parent ethynyl-estradiol. In silico docking analysis provides structural basis for the trends of ER agonism/antagonism and ER subtype selectivity. Excitingly, lead Tam-HDACi conjugates show anticancer activity that is selectively more potent against MCF-7 (ER? positive breast) compared to MDA-MB-231 (triple negative breast cancer), DU145 (prostate cancer) or Vero (non-cancerous cell line). This dual-targeting approach illustrates the utility of designing small molecules with an emphasis on cell-type selectivity, not merely improved potency, working towards a higher therapeutic index at the earliest stages of drug development. PMID:23786452

Gryder, Berkley E.; Rood, Michael K.; Johnson, Kenyetta A.; Patil, Vishal; Raftery, Eric D.; Yao, Li-Pan D.; Rice, Marcie; Azizi, Bahareh; Doyle, Donald F.; Oyelere, Adegboyega K.

2013-01-01

181

Identification of Highly Selective and Potent Histone Deacetylase 3 Inhibitors Using Click Chemistry-Based Combinatorial Fragment Assembly  

PubMed Central

To find histone deacetylase 3 (HDAC3)-selective inhibitors, a series of 504 candidates was assembled using “click chemistry”, by reacting nine alkynes bearing a zinc-binding group with 56 azide building blocks in the presence of Cu(I) catalyst. Screening of the 504-member triazole library against HDAC3 and other HDAC isozymes led to the identification of potent and selective HDAC3 inhibitors T247 and T326. These compounds showed potent HDAC3 inhibition with submicromolar IC50s, whereas they did not strongly inhibit other isozymes. Compounds T247 and T326 also induced a dose-dependent selective increase of NF-?B acetylation in human colon cancer HCT116 cells, indicating selective inhibition of HDAC3 in the cells. In addition, these HDAC3-selective inhibitors induced growth inhibition of cancer cells, and activated HIV gene expression in latent HIV-infected cells. These findings indicate that HDAC3-selective inhibitors are promising candidates for anticancer drugs and antiviral agents. This work also suggests the usefulness of the click chemistry approach to find isozyme-selective HDAC inhibitors. PMID:23874714

Suzuki, Takayoshi; Kasuya, Yuki; Itoh, Yukihiro; Ota, Yosuke; Zhan, Peng; Asamitsu, Kaori; Nakagawa, Hidehiko; Okamoto, Takashi; Miyata, Naoki

2013-01-01

182

Noninvasive Magnetic Resonance Spectroscopic Pharmacodynamic Markers of a Novel Histone Deacetylase Inhibitor, LAQ824, in Human Colon Carcinoma Cells and Xenografts1  

Microsoft Academic Search

The aim of this work was to use phosphorus magnetic resonance spectroscopy (31P MRS) to investigate the phar- macodynamic effects of LAQ824, a histone deacetylase (HDAC) inhibitor. Human HT29 colon carcinoma cells were examined by 31P MRS after treatment with LAQ824 and another HDAC inhibitor, suberoylanilide hydroxamic acid. HT29 xenografts and tumor extracts were also examined using 31P MRS, pre-

Yuen-Li Chung; Helen Troy; Rebecca Kristeleit; Wynne Aherne; L. Elizabeth Jackson; Peter Atadja; John R. Griffiths; Ian R. Judson; Paul Workman; Martin O. Leach; Mounia Beloueche-Babari

183

Design, synthesis, and biological evaluation of novel 2,4-thiazolidinedione derivatives as histone deacetylase inhibitors targeting liver cancer cell line  

Microsoft Academic Search

\\u000a Abstract  As a part of an ongoing effort to find alternate chemotherapeutic agents for hepatocellular carcinoma, we herein, report the\\u000a design and synthesis of two novel compounds targeting histone deacetylase (HDAC) with 2,4-thiazolidinedione as zinc chelating\\u000a group. Further, we demonstrate that these compounds show cytotoxicity that parallels their ability to inhibit HDACs activity\\u000a in human liver cancer cell line HepG2. The

Rhea Mohan; Ajit K. Sharma; Sanjay Gupta; C. S. Ramaa

184

HDT701, a Histone H4 Deacetylase, Negatively Regulates Plant Innate Immunity by Modulating Histone H4 Acetylation of Defense-Related Genes in Rice[W][OA  

PubMed Central

Histone acetylation and deacetylation play an important role in the modification of chromatin structure and regulation of gene expression in eukaryotes. Chromatin acetylation status is modulated antagonistically by histone acetyltransferases and histone deacetylases (HDACs). In this study, we characterized the function of histone deacetylase701 (HDT701), a member of the plant-specific HD2 subfamily of HDACs, in rice (Oryza sativa) innate immunity. Transcription of HDT701 is increased in the compatible reaction and decreased in the incompatible reaction after infection by the fungal pathogen Magnaporthe oryzae. Overexpression of HDT701 in transgenic rice leads to decreased levels of histone H4 acetylation and enhanced susceptibility to the rice pathogens M. oryzae and Xanthomonas oryzae pv oryzae (Xoo). By contrast, silencing of HDT701 in transgenic rice causes elevated levels of histone H4 acetylation and elevated transcription of pattern recognition receptor (PRR) and defense-related genes, increased generation of reactive oxygen species after pathogen-associated molecular pattern elicitor treatment, as well as enhanced resistance to both M. oryzae and Xoo. We also found that HDT701 can bind to defense-related genes to regulate their expression. Taken together, these results demonstrate that HDT701 negatively regulates innate immunity by modulating the levels of histone H4 acetylation of PRR and defense-related genes in rice. PMID:22968716

Ding, Bo; Bellizzi, Maria del Rosario; Ning, Yuese; Meyers, Blake C.; Wang, Guo-Liang

2012-01-01

185

HDT701, a histone H4 deacetylase, negatively regulates plant innate immunity by modulating histone H4 acetylation of defense-related genes in rice.  

PubMed

Histone acetylation and deacetylation play an important role in the modification of chromatin structure and regulation of gene expression in eukaryotes. Chromatin acetylation status is modulated antagonistically by histone acetyltransferases and histone deacetylases (HDACs). In this study, we characterized the function of histone deacetylase701 (HDT701), a member of the plant-specific HD2 subfamily of HDACs, in rice (Oryza sativa) innate immunity. Transcription of HDT701 is increased in the compatible reaction and decreased in the incompatible reaction after infection by the fungal pathogen Magnaporthe oryzae. Overexpression of HDT701 in transgenic rice leads to decreased levels of histone H4 acetylation and enhanced susceptibility to the rice pathogens M. oryzae and Xanthomonas oryzae pv oryzae (Xoo). By contrast, silencing of HDT701 in transgenic rice causes elevated levels of histone H4 acetylation and elevated transcription of pattern recognition receptor (PRR) and defense-related genes, increased generation of reactive oxygen species after pathogen-associated molecular pattern elicitor treatment, as well as enhanced resistance to both M. oryzae and Xoo. We also found that HDT701 can bind to defense-related genes to regulate their expression. Taken together, these results demonstrate that HDT701 negatively regulates innate immunity by modulating the levels of histone H4 acetylation of PRR and defense-related genes in rice. PMID:22968716

Ding, Bo; Bellizzi, Maria del Rosario; Ning, Yuese; Meyers, Blake C; Wang, Guo-Liang

2012-09-01

186

Pomiferin, histone deacetylase inhibitor isolated from the fruits of Maclura pomifera.  

PubMed

The major constituents from the fruits of Maclura pomifera are the prenylated isoflavones, osajin (1) and pomiferin (2). Their structures were elucidated using NMR spectroscopic techniques and mass spectrometric analysis. Compound 2 showed potential inhibitory activity in histone deacetylase (HDAC) enzyme assay. It also exhibited growth inhibitory activity on five human tumor cell lines and more sensitive inhibitory activity on the HCT-15 colon tumor cell line. Further structure-activity relationships of position 3 on ring B from aromatic ring will be reported in due course. PMID:17662606

Son, Il Hong; Chung, Ill-Min; Lee, Sung Ik; Yang, Hyun Duk; Moon, Hyung-In

2007-09-01

187

Passive Smoking Impairs Histone Deacetylase-2 in Children With Severe Asthma  

PubMed Central

Background: Parental smoking is known to worsen asthma symptoms in children and to make them refractory to asthma treatment, but the molecular mechanism is unclear. Oxidative stress from tobacco smoke has been reported to impair histone deacetylase-2 (HDAC2) via phosphoinositide-3-kinase (PI3K)/Akt activation and, thus, to reduce corticosteroid sensitivity. The aim of this study was to investigate passive smoking-dependent molecular abnormalities in alveolar macrophages (AMs) by comparing passive smoke-exposed children and non-passive smoke-exposed children with uncontrolled severe asthma. Methods: BAL fluid (BALF) was obtained from 19 children with uncontrolled severe asthma (10 non-passive smoking-exposed subjects and nine passive smoking-exposed subjects), and HDAC2 expression/activity, Akt/HDAC2 phosphorylation levels, and corticosteroid responsiveness in AMs were evaluated. Results: Parental smoking reduced HDAC2 protein expression by 54% and activity by 47%, with concomitant enhancement of phosphorylation of Akt1 and HDAC2. In addition, phosphorylation levels of Akt1 correlated positively with HDAC2 phosphorylation levels and negatively with HDAC2 activity. Furthermore, passive smoke exposure reduced the inhibitory effects of dexamethasone on tumor necrosis factor-?-induced CXCL8 release in AMs. There were relatively higher neutrophil counts and CXCL8 concentrations in BALF and lower Asthma Control Test scores compared with non-passive smoke-exposed children with uncontrolled severe asthma. Conclusions: Passive smoking impairs HDAC2 function via PI3K signaling activation, which could contribute to corticosteroid-insensitive inflammation in children with severe asthma. This novel mechanism will be a treatment target in children with severe asthma and stresses the need for a smoke-free environment for asthmatic children. PMID:24030221

Kobayashi, Yoshiki; Bossley, Cara; Gupta, Atul; Akashi, Kenichi; Tsartsali, Lemonia; Mercado, Nicolas; Barnes, Peter J.; Bush, Andrew

2014-01-01

188

Targeted cancer therapy: giving histone deacetylase inhibitors all they need to succeed  

PubMed Central

Histone deacetylase inhibitors (HDACis) have now emerged as a powerful new class of small-molecule therapeutics acting through the regulation of the acetylation states of histone proteins (a form of epigenetic modulation) and other non-histone protein targets. Over 490 clinical trials have been initiated in the last 10 years, culminating in the approval of two structurally distinct HDACis – SAHA (vorinostat, Zolinza™) and FK228 (romidepsin, Istodax™). However, the current HDACis have serious limitations, including ineffectively low concentrations in solid tumors and cardiac toxicity, which is hindering their progress in the clinic. Herein, we review the primary paradigms being pursued to overcome these hindrances, including HDAC isoform selectivity, localized administration, and targeting cap groups to achieve selective tissue and cell type distribution. PMID:22416777

Gryder, Berkley E; Sodji, Quaovi H; Oyelere, Adegboyega K

2012-01-01

189

Retinoic acid targets DNA-methyltransferases and histone deacetylases during APL blast differentiation in vitro and in vivo  

Microsoft Academic Search

The acute promyelocytic leukemia (PML)-retinoic acid receptor ? (RAR?) fusion product recruits histone deacetylase (HDAC) and DNA methyltransferase (DNMT) activities on retinoic acid (RA)-target promoters causing their silencing and differentiation block. RA treatment induces epigenetic modifications at its target loci and restores myeloid differentiation of APL blasts. Using RA-sensitive and RA-resistant APL cell lines and primary blasts, we addressed the

Francesco Fazi; Lorena Travaglini; Daniela Carotti; Franco Palitti; Daniela Diverio; Myriam Alcalay; Suzan McNamara; Wilson H Miller; Francesco Lo Coco; Pier Giuseppe Pelicci; Clara Nervi

2005-01-01

190

Nuclear Receptor Repression Mediated by a Complex Containing SMRT, mSin3A, and Histone Deacetylase  

Microsoft Academic Search

The transcriptional corepressors SMRT and N-CoR function as silencing mediators for retinoid and thyroid hormone receptors. Here we show that SMRT and N-CoR directly interact with mSin3A, a corepressor for the Mad–Max heterodimer and a homolog of the yeast global–transcriptional repressor Sin3p. In addition, we demonstrate that the recently characterized histone deacetylase 1 (HDAC1) interacts with Sin3A and SMRT to

Laszlo Nagy; Hung-Ying Kao; Debabrata Chakravarti; Richard J. Lin; Christian A. Hassig; Donald E. Ayer; Stuart L. Schreiber; Ronald M. Evans

1997-01-01

191

The Histone Deacetylase Inhibitor MS275 Interacts Synergistically with Fludarabine to Induce Apoptosis in Human Leukemia Cells  

Microsoft Academic Search

Interactions between the novel benzamide histone deacetylase (HDAC) inhibitor MS-275 and fludarabine were examined in lymphoid and mye- loid human leukemia cells in relation to mitochondrial injury, signal transduction events, and apoptosis. Prior exposure of Jurkat lymphoblas- tic leukemia cells to a marginally toxic concentration of MS-275 (e.g., 500 nM) for 24 h sharply increased mitochondrial injury, caspase activation, and

Sonia C. Maggio; Roberto R. Rosato; Lora B. Kramer; Yun Dai; Mohamed Rahmani; David S. Paik; Ann C. Czarnik; Shawn G. Payne; Sarah Spiegel; Steven Grant

2004-01-01

192

Histone deacetylase controls adult stem cell aging by balancing the expression of polycomb genes and jumonji domain containing 3  

Microsoft Academic Search

Aging is linked to loss of the self-renewal capacity of adult stem cells. Here, we observed that human multipotent stem cells\\u000a (MSCs) underwent cellular senescence in vitro. Decreased expression of histone deacetylases (HDACs), followed by downregulation\\u000a of polycomb group genes (PcGs), such as BMI1, EZH2 and SUZ12, and by upregulation of jumonji domain containing 3 (JMJD3),\\u000a was observed in senescent

Ji-Won Jung; Seunghee Lee; Min-Soo Seo; Sang-Bum Park; Andreas Kurtz; Soo-Kyung Kang; Kyung-Sun Kang

2010-01-01

193

Histone deacetylases 6 and 9 and sirtuin-1 control Foxp3+ regulatory T cell function through shared and isoform-specific mechanisms.  

PubMed

Therapeutic inhibition of the histone deacetylases HDAC6, HDAC9, or sirtuin-1 (Sirt1) augments the suppressive functions of regulatory T cells (T(regs)) that contain the transcription factor Foxp3 (Forkhead box P3) and is useful in organ transplant patients or patients with autoimmune diseases. However, it is unclear whether distinct mechanisms are involved for each HDAC or whether combined inhibition of HDACs would be more effective. We compared the suppressive functions of T(regs) from wild-type C57BL/6 mice with those from mice with either complete or cell-specific deletion of various HDACs, as well as with those of T(regs) treated with isoform-selective HDAC inhibitors. The improvement of T(reg) suppressive function mediated by inhibition of HDAC6, but not Sirt1, required an intact heat shock response. Although HDAC6, HDAC9, and Sirt1 all deacetylated Foxp3, each protein had different effects on transcription factors that control expression of the gene encoding Foxp3. For example, loss of HDAC9, but not other HDACs, was associated with stabilization of the acetylated form of signal transducer and activator of transcription 5 (STAT5) and promoted its transcriptional activity. Thus, targeting different HDACs increased T(reg) function through multiple and additive mechanisms, which suggests the therapeutic potential for using combinations of HDAC inhibitors in the management of autoimmunity and organ transplantation. PMID:22715468

Beier, Ulf H; Wang, Liqing; Han, Rongxiang; Akimova, Tatiana; Liu, Yujie; Hancock, Wayne W

2012-06-19

194

Protein Aggregates Are Recruited to Aggresome by Histone Deacetylase 6 via Unanchored Ubiquitin C Termini  

SciTech Connect

The aggresome pathway is activated when proteasomal clearance of misfolded proteins is hindered. Misfolded polyubiquitinated protein aggregates are recruited and transported to the aggresome via the microtubule network by a protein complex consisting of histone deacetylase 6 (HDAC6) and the dynein motor complex. The current model suggests that HDAC6 recognizes protein aggregates by binding directly to polyubiquitinated proteins. Here, we show that there are substantial amounts of unanchored ubiquitin in protein aggregates with solvent-accessible C termini. The ubiquitin-binding domain (ZnF-UBP) of HDAC6 binds exclusively to the unanchored C-terminal diglycine motif of ubiquitin instead of conjugated polyubiquitin. The unanchored ubiquitin C termini in the aggregates are generated in situ by aggregate-associated deubiquitinase ataxin-3. These results provide structural and mechanistic bases for the role of HDAC6 in aggresome formation and further suggest a novel ubiquitin-mediated signaling pathway, where the exposure of ubiquitin C termini within protein aggregates enables HDAC6 recognition and transport to the aggresome.

Ouyang, Hui; Ali, Yousuf O.; Ravichandran, Mani; Dong, Aiping; Qiu, Wei; MacKenzie, Farrell; Dhe-Paganon, Sirano; Arrowsmith, Cheryl H.; Zhai, R. Grace (UHN); (Toronto); (Miami-MED)

2012-07-11

195

Loop Interactions and Dynamics Tune the Enzymatic Activity of the Human Histone Deacetylase 8  

PubMed Central

The human histone deacetylase 8 (HDAC8) is a key hydrolase in gene regulation and has been identified as a drug target for the treatment of several cancers. Previously the HDAC8 enzyme has been extensively studied using biochemical techniques, X-ray crystallography, and computational methods. Those investigations have yielded detailed information about the active site and have demonstrated that the substrate entrance surface is highly dynamic. Yet it has remained unclear how the dynamics of the entrance surface tune and influence the catalytic activity of HDAC8. Using long time scale all atom molecular dynamics simulations we have found a mechanism whereby the interactions and dynamics of two loops tune the configuration of functionally important residues of HDAC8 and could therefore influence the activity of the enzyme. We subsequently investigated this hypothesis using a well-established fluorescence activity assay and a noninvasive real-time progression assay, where deacetylation of a p53 based peptide was observed by nuclear magnetic resonance spectroscopy. Our work delivers detailed insight into the dynamic loop network of HDAC8 and provides an explanation for a number of experimental observations. PMID:24171457

2013-01-01

196

Histone deacetylase inhibition increases levels of choline kinase ? and phosphocholine facilitating noninvasive imaging in human cancers.  

PubMed

Histone deacetylase (HDAC) inhibitors are currently approved for cutaneous T-cell lymphoma and are in mid-late stage trials for other cancers. The HDAC inhibitors LAQ824 and SAHA increase phosphocholine (PC) levels in human colon cancer cells and tumor xenografts as observed by magnetic resonance spectroscopy (MRS). In this study, we show that belinostat, an HDAC inhibitor with an alternative chemical scaffold, also caused a rise in cellular PC content that was detectable by (1)H and (31)P MRS in prostate and colon carcinoma cells. In addition, (1)H MRS showed an increase in branched chain amino acid and alanine concentrations. (13)C-choline labeling indicated that the rise in PC resulted from increased de novo synthesis and correlated with an induction of choline kinase ? expression. Furthermore, metabolic labeling experiments with (13)C-glucose showed that differential glucose routing favored alanine formation at the expense of lactate production. Additional analysis revealed increases in the choline/water and phosphomonoester (including PC)/total phosphate ratios in vivo. Together, our findings provide mechanistic insights into the impact of HDAC inhibition on cancer cell metabolism and highlight PC as a candidate noninvasive imaging biomarker for monitoring the action of HDAC inhibitors. PMID:22194463

Beloueche-Babari, Mounia; Arunan, Vaitha; Troy, Helen; te Poele, Robert H; te Fong, Anne-Christine Wong; Jackson, L Elizabeth; Payne, Geoffrey S; Griffiths, John R; Judson, Ian R; Workman, Paul; Leach, Martin O; Chung, Yuen-Li

2012-02-15

197

Hyperbranched polyester-based fluorescent probe for histone deacetylase via aggregation-induced emission.  

PubMed

Aberrant expression of histone deacetylases (HDACs) is related to various types of cancer and is associated with increased proliferation of tumor cells. Hence, the detection of HDAC activities is of great significance for medical sciences as well as biological diagnostics. Herein, we report a hyperbranched polyester-based one-step fluorescent assay for HDAC. This assay system consists of two water-soluble components: the hyperbranched polyester coupled with the acetylated lysine groups (H40-Lys(Ac)) and the negatively charged TPE derivative bearing two sulfonic acid groups (TPE-2SO3(-)). HDAC triggers the deacetylation of H40-Lys(Ac), thereby turning the electroneutral polymer into the positively charged one. Consequently, complexation occurs between the positively charged polymer and the negatively charged TPE-2SO3(-), thereby leading to the formation of nanoaggregates due to electrostatic interaction. Eventually, the fluorescence enhancement as a result of AIE effect is achieved. This assay system is operable in aqueous media with very low detection limit of 25 ng/mL. The system is capable of detecting HDAC in such biological fluid as serum, and this strategy may provide a new and effective approach for enzyme assay. PMID:24251690

Yu, Changmin; Wu, Yinglong; Zeng, Fang; Li, Xizhen; Shi, Jianbin; Wu, Shuizhu

2013-12-01

198

Histone deacetylase inhibition destabilizes the multi-potent state of uncommitted adipose-derived mesenchymal stromal cells.  

PubMed

Human adipose-derived mesenchymal stromal cells (AMSCs) grown in platelet lysate are promising agents for therapeutic tissue regeneration. Here, we investigated whether manipulation of epigenetic events by the clinically relevant histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) alters differentiation of AMSCs. The multipotency of AMSCs was validated by their ability to differentiate into osteogenic, chondrogenic, and adipogenic lineages. High-throughput RNA sequencing and RT-qPCR established that human histone deacetylases (HDAC1 to HDAC11, and SIRT1 to SIRT7) are differentially expressed in AMSCs. SAHA induces hyper-acetylation of histone H3 and H4, stimulates protein expression of the HDAC-responsive gene SLC9A3R1/NHERF1 and modulates the AKT/FOXO1 pathway. Biologically, SAHA interferes with osteogenic, chondrogenic and adipogenic lineage commitment of multipotent AMSCs. Mechanistically, SAHA-induced loss of differentiation potential of uncommitted AMSCs correlates with multiple changes in the expression of principal transcription factors that control mesenchymal or pluripotent states. We propose that SAHA destabilizes the multi-potent epigenetic state of uncommitted human AMSCs by hyper-acetylation and perturbation of key transcription factor pathways. Furthermore, AMSCs grown in platelet lysate may provide a useful biological model for screening of new HDAC inhibitors that control the biological fate of human mesenchymal stromal cells. PMID:24912092

Dudakovic, Amel; Camilleri, Emily T; Lewallen, Eric A; McGee-Lawrence, Meghan E; Riester, Scott M; Kakar, Sanjeev; Montecino, Martin; Stein, Gary S; Ryoo, Hyun-Mo; Dietz, Allan B; Westendorf, Jennifer J; van Wijnen, Andre J

2015-01-01

199

Plant Polyphenols and Oxidative Metabolites of the Herbal Alkenylbenzene Methyleugenol Suppress Histone Deacetylase Activity in Human Colon Carcinoma Cells  

PubMed Central

Evidence has been provided that diet and environmental factors directly influence epigenetic mechanisms associated with cancer development in humans. The inhibition of histone deacetylase (HDAC) activity and the disruption of the HDAC complex have been recognized as a potent strategy for cancer therapy and chemoprevention. In the present study, we investigated whether selected plant constituents affect HDAC activity or HDAC1 protein status in the human colon carcinoma cell line HT29. The polyphenols (?)-epigallocatechin-3-gallate (EGCG) and genistein (GEN) as well as two oxidative methyleugenol (ME) metabolites were shown to inhibit HDAC activity in intact HT29 cells. Concomitantly, a significant decrease of the HDAC1 protein level was observed after incubation with EGCG and GEN, whereas the investigated ME metabolites did not affect HDAC1 protein status. In conclusion, dietary compounds were found to possess promising HDAC-inhibitory properties, contributing to epigenetic alterations in colon tumor cells, which should be taken into account in further risk/benefit assessments of polyphenols and alkenylbenzenes. PMID:23476753

Groh, Isabel Anna Maria; Chen, Chen; Lüske, Claudia; Cartus, Alexander Thomas; Esselen, Melanie

2013-01-01

200

Differential expression of histone deacetylase and acetyltransferase genes in gastric cancer and their modulation by trichostatin A.  

PubMed

Gastric cancer is still the second leading cause of cancer-related death worldwide, even though its incidence and mortality have declined over the recent few decades. Epigenetic control using histone deacetylase inhibitors, such as trichostatin A (TSA), is a promising cancer therapy. This study aimed to assess the messenger RNA (mRNA) levels of three histone deacetylases (HDAC1, HDAC2, and HDAC3), two histone acetyltransferases (GCN5 and PCAF), and two possible targets of these histone modifiers (MYC and CDKN1A) in 50 matched pairs of gastric tumors and corresponding adjacent nontumors samples from patients with gastric adenocarcinoma, as well as their correlations and their possible associations with clinicopathological features. Additionally, we evaluated whether these genes are sensitive to TSA in gastric cancer cell lines. Our results demonstrated downregulation of HDAC1, PCAF, and CDKN1A in gastric tumors compared with adjacent nontumors (P < 0.05). On the other hand, upregulation of HDAC2, GCN5, and MYC was observed in gastric tumors compared with adjacent nontumors (P < 0.05). The mRNA level of MYC was correlated to HDAC3 and GCN5 (P < 0.05), whereas CDKN1A was correlated to HDAC1 and GCN5 (P < 0.05 and P < 0.01, respectively). In addition, the reduced expression of PCAF was associated with intestinal-type gastric cancer (P = 0.03) and TNM stages I/II (P = 0.01). The increased expression of GCN5 was associated with advanced stage gastric cancer (P = 0.02) and tumor invasion (P = 0.03). The gastric cell lines treated with TSA showed different patterns of histone deacetylase and acetyltransferase mRNA expression, downregulation of MYC, and upregulation of CDKN1A. Our findings suggest that alteration of histone modifier genes play an important role in gastric carcinogenesis, contributing to MYC and CDKN1A deregulation. In addition, all genes studied here are modulated by TSA, although this modulation appears to be dependent of the genetic background of the cell line. PMID:24668547

Wisnieski, Fernanda; Calcagno, Danielle Queiroz; Leal, Mariana Ferreira; Chen, Elizabeth Suchi; Gigek, Carolina Oliveira; Santos, Leonardo Caires; Pontes, Thaís Brilhante; Rasmussen, Lucas Trevizani; Payão, Spencer Luiz Marques; Assumpção, Paulo Pimentel; Lourenço, Laércio Gomes; Demachki, Sâmia; Artigiani, Ricardo; Burbano, Rommel Rodríguez; Smith, Marília Cardoso

2014-07-01

201

Sulforaphane inhibits histone deacetylase activity in BPH-1, LnCaP and PC-3 prostate epithelial cells  

PubMed Central

Sulforaphane (SFN), an isothiocyanate first isolated from broccoli, exhibits chemopreventive properties in prostate cancer cells through mechanisms that are poorly understood. We recently reported on a novel mechanism of chemoprotection by SFN in human colon cancer cells, namely the inhibition of histone deacetylase (HDAC). Here, we show that addition of 15 ?M SFN also inhibited HDAC activity by 40, 30 and 40% in BPH-1, LnCaP and PC-3 prostate epithelial cells, respectively. The inhibition of HDAC was accompanied by a 50–100% increase in acetylated histones in all three prostate cell lines, and in BPH-1 cells treated with SFN there was enhanced interaction of acetylated histone H4 with the promoter region of the P21 gene and the bax gene. A corresponding 1.5- to 2-fold increase was seen for p21Cip1/Waf1 and Bax protein expression, consistent with previous studies using HDAC inhibitors, such as trichostatin A. The downstream events included cell cycle arrest and activation of apoptosis, as evidenced by changes in cell cycle kinetics and induction of multi-caspase activity. These findings provide new insight into the mechanisms of SFN action in benign prostate hyperplasia, androgen-dependent prostate cancer and androgen-independent prostate cancer cells, and they suggest a novel approach to chemoprotection and chemotherapy of prostate cancer through the inhibition of HDAC. PMID:16280330

Myzak, Melinda C.; Hardin, Karin; Wang, Rong; Dashwood, Roderick H.; Ho, Emily

2008-01-01

202

Antitumor Action of a Novel Histone Deacetylase Inhibitor, YF479, in Breast Cancer1  

PubMed Central

Accumulating evidence demonstrates important roles for histone deacetylase in tumorigenesis (HDACs), highlighting them as attractive targets for antitumor drug development. Histone deactylase inhibitors (HDACIs), which have shown favorable anti-tumor activity with low toxicity in clinical investigations, are a promising class of anticancer therapeutics. Here, we screened our compound library to explore small molecules that possess anti-HDAC activity and identified a novel HDACI, YF479. Suberoylanilide hydroxamic acid (SAHA), which was the first approved HDAC inhibitor for clinical treatment by the FDA, was as positive control in our experiments. We further demonstrated YF479 abated cell viability, suppressed colony formation and tumor cell motility in vitro. To investigate YF479 with superior pharmacodynamic properties, we developed spontaneous and experimental breast cancer animal models. Our results showed YF479 significantly inhibited breast tumor growth and metastasis in vivo. Further study indicated YF479 suppressed both early and end stages of metastatic progression. Subsequent adjuvant chemotherapy animal experiment revealed the elimination of local-regional recurrence (LRR) and distant metastasis by YF479. More important, YF479 remarkably prolonged the survival of tumor-bearing mice. Intriguingly, YF479 displayed more potent anti-tumor activity in vitro and in vivo compared with SAHA. Together, our results suggest that YF479, a novel HDACI, inhibits breast tumor growth, metastasis and recurrence. In light of these results, YF479 may be an effective therapeutic option in clinical trials for patients burdened by breast cancer. PMID:25220594

Zhang, Tao; Chen, Yihua; Li, Jingjie; Yang, Feifei; Wu, Haigang; Dai, Fujun; Hu, Meichun; Lu, Xiaoling; Peng, Yi; Liu, Mingyao; Zhao, Yongxiang; Yi, Zhengfang

2014-01-01

203

Antitumor action of a novel histone deacetylase inhibitor, YF479, in breast cancer.  

PubMed

Accumulating evidence demonstrates important roles for histone deacetylase in tumorigenesis (HDACs), highlighting them as attractive targets for antitumor drug development. Histone deactylase inhibitors (HDACIs), which have shown favorable anti-tumor activity with low toxicity in clinical investigations, are a promising class of anticancer therapeutics. Here, we screened our compound library to explore small molecules that possess anti-HDAC activity and identified a novel HDACI, YF479. Suberoylanilide hydroxamic acid (SAHA), which was the first approved HDAC inhibitor for clinical treatment by the FDA, was as positive control in our experiments. We further demonstrated YF479 abated cell viability, suppressed colony formation and tumor cell motility in vitro. To investigate YF479 with superior pharmacodynamic properties, we developed spontaneous and experimental breast cancer animal models. Our results showed YF479 significantly inhibited breast tumor growth and metastasis in vivo. Further study indicated YF479 suppressed both early and end stages of metastatic progression. Subsequent adjuvant chemotherapy animal experiment revealed the elimination of local-regional recurrence (LRR) and distant metastasis by YF479. More important, YF479 remarkably prolonged the survival of tumor-bearing mice. Intriguingly, YF479 displayed more potent anti-tumor activity in vitro and in vivo compared with SAHA. Together, our results suggest that YF479, a novel HDACI, inhibits breast tumor growth, metastasis and recurrence. In light of these results, YF479 may be an effective therapeutic option in clinical trials for patients burdened by breast cancer. PMID:25220594

Zhang, Tao; Chen, Yihua; Li, Jingjie; Yang, Feifei; Wu, Haigang; Dai, Fujun; Hu, Meichun; Lu, Xiaoling; Peng, Yi; Liu, Mingyao; Zhao, Yongxiang; Yi, Zhengfang

2014-08-01

204

Anticolon Cancer Activity of Largazole, a Marine-Derived Tunable Histone Deacetylase InhibitorS?  

PubMed Central

Histone deacetylases (HDACs) are validated targets for anticancer therapy as attested by the approval of suberoylanilide hydroxamic acid (SAHA) and romidepsin (FK228) for treating cutaneous T cell lymphoma. We recently described the bioassay-guided isolation, structure determination, synthesis, and target identification of largazole, a marine-derived antiproliferative natural product that is a prodrug that releases a potent HDAC inhibitor, largazole thiol. Here, we characterize the anticancer activity of largazole by using in vitro and in vivo cancer models. Screening against the National Cancer Institute's 60 cell lines revealed that largazole is particularly active against several colon cancer cell types. Consequently, we tested largazole, along with several synthetic analogs, for HDAC inhibition in human HCT116 colon cancer cells. Enzyme inhibition strongly correlated with the growth inhibitory effects, and differential activity of largazole analogs was rationalized by molecular docking to an HDAC1 homology model. Comparative genomewide transcript profiling revealed a close overlap of genes that are regulated by largazole, FK228, and SAHA. Several of these genes can be related to largazole's ability to induce cell cycle arrest and apoptosis. Stability studies suggested reasonable bioavailability of the active species, largazole thiol. We established that largazole inhibits HDACs in tumor tissue in vivo by using a human HCT116 xenograft mouse model. Largazole strongly stimulated histone hyperacetylation in the tumor, showed efficacy in inhibiting tumor growth, and induced apoptosis in the tumor. This effect probably is mediated by the modulation of levels of cell cycle regulators, antagonism of the AKT pathway through insulin receptor substrate 1 down-regulation, and reduction of epidermal growth factor receptor levels. PMID:20739454

Liu, Yanxia; Salvador, Lilibeth A.; Byeon, Seongrim; Ying, Yongcheng; Kwan, Jason C.; Law, Brian K.; Hong, Jiyong

2010-01-01

205

Antidepressants and mood stabilizers effects on histone deacetylase expression in C57BL/6 mice: Brain region specific changes.  

PubMed

To determine whether treatment with various antidepressants or mood stabilizers leads to region-specific changes, we investigated the effects of their subchronic (14 days of intraperitoneal injection) administration on the tissue concentration of monoamines, dopamine, serotonin, and norepinephrine, and the protein expression of acetylated histone H3 (AcH3) and histone deacetylases (HDACs) in the mouse striatum (ST), nucleus accumbens (Acb), hippocampus (Hip), cingulate cortex (Cg), and amygdala (Amy). Subchronic administration with the antidepressants (S)-citalopram oxalate (ECM), duloxetine hydrochloride (DLX), and mirtazapine (MIR) commonly induced significant increases in dopamine and serotonin levels in the ST and Cg. By contrast, no common profiles for dopamine, serotonin, or norepinephrine were identified in the Acb, Hip, or Amy. Treatment with sodium valproate (VPA), lithium chloride (Li), lamotrigine (LTG), levetiracetam (LTM), olanzapine (OLZ), clozapine (CLZ), clomipramine (CLM), ECM, and DLX induced significant increases in AcH3 expression in the Acb, while treatment with CLM, ECM, DLX, MIR, carbamazepine (CBZ), LTG, LTM, OLZ, or CLZ induced significant increases in HDAC2 and HDAC3 in the ST. CLM, MIR, VPA, CBZ, LTG, LTM, OLZ, or CLZ induced significant increases in HDAC3 in the Cg, and ECM, DLX, MIR, VPA, CBZ, LTG, LTM, or OLZ resulted in significant increases in HDAC5 in the Amy. Collectively, the changes of monoamine content were restricted for mood stabilizer effects, but increased expression of HDAC2, HDAC3, or HDAC5 in the ST, Cg, or Amy was often found, supporting the possibility that antidepressant-like effects involve epigenetic modifications associated with changes in HDAC expression. PMID:23777937

Ookubo, Masanori; Kanai, Hirohiko; Aoki, Harusuke; Yamada, Naoto

2013-09-01

206

Suberoylanilide hydroxamic acid (SAHA)-induced dynamics of a human histone deacetylase protein interaction network.  

PubMed

Histone deacetylases (HDACs) are targets for cancer therapy. Suberoylanilide hydroxamic acid (SAHA) is an HDAC inhibitor approved by the U.S. Food and Drug Administration for the treatment of cutaneous T-cell lymphoma. To obtain a better mechanistic understanding of the Sin3/HDAC complex in cancer, we extended its protein-protein interaction network and identified a mutually exclusive pair within the complex. We then assessed the effects of SAHA on the disruption of the complex network through six homologous baits. SAHA perturbs multiple protein interactions and therefore compromises the composition of large parts of the Sin3/HDAC network. A comparison of the effect of SAHA treatment on gene expression in breast cancer cells to a knockdown of the ING2 subunit indicated that a portion of the anticancer effects of SAHA may be attributed to the disruption of ING2's association with the complex. Our dynamic protein interaction network resource provides novel insights into the molecular mechanism of SAHA action and demonstrates the potential for drugs to rewire networks. PMID:25073741

Sardiu, Mihaela E; Smith, Karen T; Groppe, Brad D; Gilmore, Joshua M; Saraf, Anita; Egidy, Rhonda; Peak, Allison; Seidel, Chris W; Florens, Laurence; Workman, Jerry L; Washburn, Michael P

2014-11-01

207

Emodin inhibits proinflammatory responses and inactivates histone deacetylase 1 in hypoxic rheumatoid synoviocytes.  

PubMed

Chronic inflammation of rheumatoid arthritis (RA) is promoted by proinflammatory cytokines and closely linked to angiogenesis. In the present study, we investigated the anti-inflammatory effects of emodin (1,3,8-trihydroxy-6-methyl-anthraquinone) isolated from the root of Rheum palmatum L. in interleukin 1 beta (IL-1?) and lipopolysaccharide (LPS)-stimulated RA synoviocytes under hypoxia. Emodin significantly inhibited IL-1? and LPS-stimulated proliferation of RA synoviocytes in a dose-dependent manner under hypoxic condition. Also, enzyme linked immunosorbent assay (ELISA) revealed that emodin significantly reduced the production of pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-?), IL-6 and IL-8], mediators [prostagladin E(2) (PGE(2)), matrix metalloproteinase (MMP)-1 and MMP-13] and vascular endothelial growth factor (VEGF) as an angiogenesis biomarker in IL-1? and LPS-treated synoviocytes under hypoxia. Consistently, emodin attenuated the expression of cyclooxygenase 2 (COX-2), VEGF, hypoxia inducible factor 1 alpha (HIF-1?), MMP-1 and MMP-13 at mRNA level in IL-1? and LPS-treated synoviocytes under hypoxia. Furthermore, emodin reduced histone deacetylase (HDAC) activity as well as suppressed the expression of HDAC1, but not HDAC2 in IL-1? and LPS-treated synoviocytes under hypoxia. Overall, these findings suggest that emodin inhibits proinflammatory cytokines and VEGF productions, and HDAC1 activity in hypoxic RA synoviocytes. PMID:21881229

Ha, Mi-Kyoung; Song, Young Hoon; Jeong, Soo-Jin; Lee, Hyo-Jung; Jung, Ji Hoon; Kim, Bonglee; Song, Hyo Sook; Huh, Jeong-Eun; Kim, Sung-Hoon

2011-01-01

208

HDAC6 Deacetylase Activity Is Critical for Lipopolysaccharide-Induced Activation of Macrophages  

PubMed Central

Activated macrophages play an important role in both innate and adaptive immune responses, and aberrant activation of macrophages often leads to inflammatory and immune disorders. However, the molecular mechanisms of how macrophages are activated are not fully understood. In this study, we identify a novel role for histone deacetylse 6 (HDAC6) in lipopolysaccharide (LPS)-induced macrophage activation. Our data show that suppression of HDAC6 activity significantly restrains LPS-induced activation of macrophages and production of pro-inflammatory cytokines. Further study reveals that the regulation of macrophage activation by HDAC6 is independent of F-actin polymerization and filopodium formation; instead, it is mediated by the effects of HDAC6 on cell adhesion and microtubule acetylation. These data thus suggest that HDAC6 is an important regulator of LPS-induced macrophage activation and might be a potential target for the management of inflammatory disorders. PMID:25330030

Liu, Zhu; Ran, Jie; Li, Yuanyuan; Wang, Jian; Yang, Yang; Zhou, Jun; Li, Dengwen; Liu, Min

2014-01-01

209

Inhibition of Glyceroneogenesis by Histone Deacetylase 3 Contributes to Lipodystrophy in Mice with Adipose Tissue Inflammation  

PubMed Central

We have reported that the nuclear factor-?B (NF-?B) induces chronic inflammation in the adipose tissue of p65 transgenic (Tg) mice, in which the NF-?B subunit p65 (RelA) is overexpressed from the adipocyte protein 2 (aP2) gene promoter. Tg mice suffer a mild lipodystrophy and exhibit deficiency in adipocyte differentiation. To understand molecular mechanism of the defect in adipocytes, we investigated glyceroneogenesis by examining the activity of cytosolic phosphoenolpyruvate carboxykinase (PEPCK) in adipocytes. In aP2-p65 Tg mice, Pepck expression is inhibited at both the mRNA and protein levels in adipose tissue. The mRNA reduction is a consequence of transcriptional inhibition but not alteration in mRNA stability. The Pepck gene promoter is inhibited by NF-?B, which enhances the corepressor activity through activation of histone deacetylase 3 (HDAC3) in the nucleus. HDAC3 suppresses Pepck transcription by inhibiting the transcriptional activators, peroxisome proliferator-activated receptor-?, and cAMP response element binding protein. The NF-?B activity is abolished by Hdac3 knockdown or inhibition of HDAC3 catalytic activity. In a chromatin immunoprecipitation assay, HDAC3 interacts with peroxisome proliferator-activated receptor-? and cAMP response element binding protein in the Pepck promoter when NF-?B is activated by TNF-?. These results suggest that HDAC3 mediates NF-?B activity to repress Pepck transcription. This mechanism is responsible for inhibition of glyceroneogenesis in adipocytes, which contributes to lipodystrophy in the aP2-p65 Tg mice. PMID:21406501

Zhang, Jin; Henagan, Tara M.; Gao, Zhanguo

2011-01-01

210

Decreased histone deacetylase 2 impairs Nrf2 activation by oxidative stress  

PubMed Central

Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a crucial role in cellular defence against oxidative stress by inducing the expression of multiple anti-oxidant genes. However, where high levels of oxidative stress are observed, such as chronic obstructive pulmonary disease (COPD), Nrf2 activity is reduced, although the molecular mechanism for this defect is uncertain. Here, we show that down-regulation of histone deacetylase (HDAC) 2 causes Nrf2 instability, resulting in reduced anti-oxidant gene expression and increase sensitivity to oxidative stress. Although Nrf2 protein was clearly stabilized after hydrogen peroxide (H2O2) stimulation in a bronchial epithelial cell line (BEAS2B), Nrf2 stability was decreased and Nrf2 acetylation increased in the presence of an HDAC inhibitor, trichostatin A (TSA). TSA also reduced Nrf2-regulated heme-oxygenase-1 (HO-1) expression in these cells, and this was confirmed in acute cigarette-smoke exposed mice in vivo. HDAC2 knock-down by RNA interference resulted in reduced H2O2-induced Nrf2 protein stability and activity in BEAS2B cells, whereas HDAC1 knockdown had no effect. Furthermore, monocyte-derived macrophages obtained from healthy volunteers (non-smokers and smokers) and COPD patients showed a significant correlation between HDAC2 expression and Nrf2 expression (r = 0.92, p < 0.0001). Thus, reduced HDAC2 activity in COPD may account for increased Nrf2 acetylation, reduced Nrf2 stability and impaired anti oxidant defences. PMID:21320471

Mercado, Nicolas; Thimmulappa, Rajesh; Thomas, Catherine M.R.; Fenwick, Peter S.; Chana, Kirandeep K.; Donnelly, Louise E.; Biswal, Shyam; Ito, Kazuhiro; Barnes, Peter J.

2011-01-01

211

Senescence delay and repression of p16INK4a by Lsh via recruitment of histone deacetylases in human diploid fibroblasts  

PubMed Central

Lymphoid specific helicase (Lsh) belongs to the family of SNF2/helicases. Disruption of Lsh leads to developmental growth retardation and premature aging in mice. However, the specific effect of Lsh on human cellular senescence remains unknown. Herein, we report that Lsh overexpression delays cell senescence by silencing p16INK4a in human fibroblasts. The patterns of p16INK4a and Lsh expression during cell senescence present the inverse correlation. We also find that Lsh requires histone deacetylase (HDAC) activity to repress p16INK4a and treatment with trichostatin A (TSA) is sufficient to block the repressor effect of Lsh. Moreover, overexpression of Lsh is correlated with deacetylation of histone H3 at the p16 promoter, and TSA treatment in Lsh-expressing cells reverses the acetylation status of histones. Additionally, we demonstrate an interaction between Lsh, histone deacetylase 1 (HDAC1) and HDAC2 in vivo. Furthermore, we demonstrate that Lsh interacts in vivo with the p16 promoter and recruits HDAC1. Our data suggest that Lsh represses endogenous p16INK4a expression by recruiting HDAC to establish a repressive chromatin structure at the p16INK4a promoter, which in turn delays cell senescence. PMID:19561196

Zhou, Rui; Han, Limin; Li, Guodong; Tong, Tanjun

2009-01-01

212

Epigenetic targeting of histone deacetylase: therapeutic potential in Parkinson's disease?  

PubMed

Parkinson's disease (PD) is the most common movement disorder affecting more than 4million people worldwide. The primary motor symptoms of the disease are due to degeneration of dopaminergic nigrostriatal neurons. Dopamine replacement therapies have therefore revolutionised disease management by partially controlling these symptoms. However these drugs can produce debilitating side effects when used long term and do not protect degenerating neurons against death. Recent evidence has highlighted a pathological imbalance in PD between the acetylation and deacetylation of the histone proteins around which deoxyribonucleic acid (DNA) is coiled, in favour of excessive histone deacetylation. This mechanism of adding/removing acetyl groups to histone lysine residues is one of many epigenetic regulatory processes which control the expression of genes, many of which will be essential for neuronal survival. Hence, such epigenetic modifications may have a pathogenic role in PD. It has therefore been hypothesised that if this pathological imbalance can be corrected with the use of histone deacetylase inhibiting agents then neurodegeneration observed in PD can be ameliorated. This article will review the current literature with regard to epigenetic changes in PD and the use of histone deacetylase inhibitors (HDACIs) in PD: examining the evidence of the neuroprotective effects of numerous HDACIs in cellular and animal models of Parkinsonian cell death. Ultimately answering the question: does epigenetic targeting of histone deacetylases hold therapeutic potential in PD? PMID:23711791

Harrison, Ian F; Dexter, David T

2013-10-01

213

[Histone deacetylases: a new class of efficient anti-tumor drugs].  

PubMed

Circa twenty-five years ago, cancer research was dominated by the concept that the origin of cancer was genetic. Thousands of genetic alterations have indeed been identified involving more than hundred different genes in cancer development. Today, the model has evolved: it has been demonstrated that malignancies can be initiated not only through genetic alterations but also through epigenetic deregulations. By altering the expression of gene involved in cell regulation, epigenetic alterations, such as histone acetylation, play a key role in the initiation and progression of neoplasm. It has been shown that an imbalance between the acelylated and deacetylated status of chromatin is significantly involved in the acquisition of a malignant phenotype. Thus, the modulation of the histone acetylation level by histone deacetylase (HDAC) inhibitors could lead to a genetic re-programmation in cancer cells that would favor apoptosis and prevent proliferation. The potential therapeutic value of several HDAC inhibitors for cancer patients has been evaluated in clinical assays with very promising outcome. Indeed, the first inhibitors available for patients has been recently approved for cancer patients tracing the way for a new class of promising anti-cancer therapy modalities. PMID:18789222

Mottet, Denis; Castronovo, Vincent

2008-01-01

214

Rationale for the Development of 2-Aminobenzamide Histone Deacetylase Inhibitors as Therapeutics for Friedreich Ataxia  

PubMed Central

Numerous studies have pointed to histone deacetylase inhibitors as potential therapeutics for various neurodegenerative diseases, and clinical trials with several histone deacetylase inhibitors have been performed or are underway. However, histone deacetylase inhibitors tested to date are either highly cytotoxic or have very low specificities for different histone deacetylase enzymes. Our laboratories have identified a novel class of histone deacetylase inhibitors (2-aminobenzamides) that reverses heterochromatin-mediated silencing of the frataxin (FXN) gene in Friedreich ataxia. We have identified the histone deacetylase enzyme isotype target of these compounds and present evidence that compounds that target this enzyme selectively increase FXN expression from pathogenic alleles. Studies with model compounds show that these histone deacetylase inhibitors increase FXN messenger RNA levels in the brain in mouse models for Friedreich ataxia, relieve neurological symptoms observed in one mouse model, and support the notion that this class of molecules may serve as therapeutics for the human disease. PMID:22764181

Soragni, Elisabetta; Xu, Chunping; Plasterer, Heather L.; Jacques, Vincent; Rusche, James R.; Gottesfeld, Joel M.

2013-01-01

215

In Silico Investigation of Traditional Chinese Medicine Compounds to Inhibit Human Histone Deacetylase 2 for Patients with Alzheimer's Disease  

PubMed Central

Human histone deacetylase 2 (HDAC2) has been identified as being associated with Alzheimer's disease (AD), a neuropathic degenerative disease. In this study, we screen the world's largest Traditional Chinese Medicine (TCM) database for natural compounds that may be useful as lead compounds in the search for inhibitors of HDAC2 function. The technique of molecular docking was employed to select the ten top TCM candidates. We used three prediction models, multiple linear regression (MLR), support vector machine (SVM), and the Bayes network toolbox (BNT), to predict the bioactivity of the TCM candidates. Molecular dynamics simulation provides the protein-ligand interactions of compounds. The bioactivity predictions of pIC50 values suggest that the TCM candidatesm, (?)-Bontl ferulate, monomethylcurcumin, and ningposides C, have a greater effect on HDAC2 inhibition. The structure variation caused by the hydrogen bonds and hydrophobic interactions between protein-ligand interactions indicates that these compounds have an inhibitory effect on the protein. PMID:25045700

Hung, Tzu-Chieh; Lee, Wen-Yuan; Chen, Kuen-Bao; Chan, Yueh-Chiu; Lee, Cheng-Chun

2014-01-01

216

Alpha-keto acid metabolites of naturally occurring organoselenium compounds as inhibitors of histone deacetylase in human prostate cancer cells.  

PubMed

Histone deacetylase (HDAC) inhibitors are gaining interest as cancer therapeutic agents. We tested the hypothesis that natural organoselenium compounds might be metabolized to HDAC inhibitors in human prostate cancer cells. Se-Methyl-L-selenocysteine (MSC) and selenomethionine are amino acid components of selenium-enriched yeast. In a cell-free system, glutamine transaminase K (GTK) and L-amino acid oxidase convert MSC to the corresponding alpha-keto acid, beta-methylselenopyruvate (MSP), and L-amino acid oxidase converts selenomethionine to its corresponding alpha-keto acid, alpha-keto-gamma-methylselenobutyrate (KMSB). Although methionine (sulfur analogue of selenomethionine) is an excellent substrate for GTK, selenomethionine is poorly metabolized. Structurally, MSP and KMSB resemble the known HDAC inhibitor butyrate. We examined androgen-responsive LNCaP cells and androgen-independent LNCaP C4-2, PC-3, and DU145 cells and found that these human prostate cancer cells exhibit endogenous GTK activities. In the corresponding cytosolic extracts, the metabolism of MSC was accompanied by the concomitant formation of MSP. In MSP-treated and KMSB-treated prostate cancer cell lines, acetylated histone 3 levels increased within 5 hours, and returned to essentially baseline levels by 24 hours, suggesting a rapid, transient induction of histone acetylation. In an in vitro HDAC activity assay, the selenoamino acids, MSC and selenomethionine, had no effect at concentrations up to 2.5 mmol/L, whereas MSP and KMSB both inhibited HDAC activity. We conclude that, in addition to targeting redox-sensitive signaling proteins and transcription factors, alpha-keto acid metabolites of MSC and selenomethionine can alter HDAC activity and histone acetylation status. These findings provide a potential new paradigm by which naturally occurring organoselenium might prevent the progression of human prostate cancer. PMID:19584079

Lee, Jeong-In; Nian, Hui; Cooper, Arthur J L; Sinha, Raghu; Dai, Jenny; Bisson, William H; Dashwood, Roderick H; Pinto, John T

2009-07-01

217

Histone deacetylase inhibitor LBH589 reactivates silenced estrogen receptor alpha (ER) gene expression without loss of DNA hypermethylation.  

PubMed

Our previous studies demonstrated that inhibition of histone deacetylases (HDACs) by trichostatin A reactivates estrogen receptor alpha (ER) gene expression in ER-negative breast cancer cells. Here, we use the clinically relevant HDAC inhibitor, LBH589 (LBH) to explore the roles of HDAC in ER gene silencing. In the ER-negative human breast cancer lines, MDA-MB-231 and MDA-MB-435, treatment with LBH for 24 hours restored ER mRNA and protein expression without a concomitant demethylation of the CpG island at the ER promoter. The expression of ER mRNA was sustained at least 96 hours after withdrawal of LBH treatment. Restoration of ER expression by LBH enhanced 4-hydroxy-tamoxifen sensitivity in MDA-MB-231 cells. The molecular mechanisms by which LBH reactivated silenced ER gene in MDA-MB-231 cells were examined with emphasis on chromatin structure reorganization. By chromatin immunoprecipitation analysis, LBH treatment released DNMT1, HDAC1, and the H3 lysine 9 (H3-K9) methyltransferase SUV39H 1 from the ER promoter. Such changes were associated with an active chromatin formation manifested as accumulation of acetylated histones H3 and H4, a decrease in methylated H3-K9, and an impaired binding of heterochromatin protein 1 (HP1 alpha) at the promoter. Our findings suggest that HDAC inhibitors could restore expression of the silenced ER gene by reorganizing the heterochromatin-associated proteins without alteration in promoter DNA hypermethylation. PMID:17172825

Zhou, Qun; Atadja, Peter; Davidson, Nancy E

2007-01-01

218

Histone Deacetylase Inhibitors and Mithramycin A Impact a Similar Neuroprotective Pathway at a Crossroad between Cancer and Neurodegeneration.  

PubMed

Mithramycin A (MTM) and histone deacetylase inhibitors (HDACi) are effective therapeutic agents for cancer and neurodegenerative diseases. MTM is a FDA approved aureolic acid-type antibiotic that binds to GC-rich DNA sequences and interferes with Sp1 transcription factor binding to its target sites (GC box). HDACi, on the other hand, modulate the activity of class I and II histone deacetylases. They mediate their protective function, in part, by regulating the acetylation status of histones or transcription factors, including Sp1, and in turn chromatin accessibility to the transcriptional machinery. Because these two classes of structurally and functionally diverse compounds mediate similar therapeutic functions, we investigated whether they act on redundant or synergistic pathways to protect neurons from oxidative death. Non-protective doses of each of the drugs do not synergize to create resistance to oxidative death suggesting that these distinct agents act via a similar pathway. Accordingly, we found that protection by MTM and HDACi is associated with diminished expression of the oncogene, Myc and enhanced expression of a tumor suppressor, p21(waf1/cip1). We also find that neuroprotection by MTM or Myc knockdown is associated with downregulation of class I HDAC levels. Our results support a model in which the established antitumor drug MTM or canonical HDACi act via distinct mechanisms to converge on the downregulation of HDAC levels or activity respectively. These findings support the conclusion that an imbalance in histone acetylase and HDAC activity in favor of HDACs is key not only for oncogenic transformation, but also neurodegeneration. PMID:22582024

Sleiman, Sama F; Berlin, Jill; Basso, Manuela; Karuppagounder, Saravanan S; Rohr, Jürgen; Ratan, Rajiv R

2011-08-22

219

Histone Deacetylase Inhibitors and Mithramycin A Impact a Similar Neuroprotective Pathway at a Crossroad between Cancer and Neurodegeneration  

PubMed Central

Mithramycin A (MTM) and histone deacetylase inhibitors (HDACi) are effective therapeutic agents for cancer and neurodegenerative diseases. MTM is a FDA approved aureolic acid-type antibiotic that binds to GC-rich DNA sequences and interferes with Sp1 transcription factor binding to its target sites (GC box). HDACi, on the other hand, modulate the activity of class I and II histone deacetylases. They mediate their protective function, in part, by regulating the acetylation status of histones or transcription factors, including Sp1, and in turn chromatin accessibility to the transcriptional machinery. Because these two classes of structurally and functionally diverse compounds mediate similar therapeutic functions, we investigated whether they act on redundant or synergistic pathways to protect neurons from oxidative death. Non-protective doses of each of the drugs do not synergize to create resistance to oxidative death suggesting that these distinct agents act via a similar pathway. Accordingly, we found that protection by MTM and HDACi is associated with diminished expression of the oncogene, Myc and enhanced expression of a tumor suppressor, p21waf1/cip1. We also find that neuroprotection by MTM or Myc knockdown is associated with downregulation of class I HDAC levels. Our results support a model in which the established antitumor drug MTM or canonical HDACi act via distinct mechanisms to converge on the downregulation of HDAC levels or activity respectively. These findings support the conclusion that an imbalance in histone acetylase and HDAC activity in favor of HDACs is key not only for oncogenic transformation, but also neurodegeneration. PMID:22582024

Sleiman, Sama F.; Berlin, Jill; Basso, Manuela; S.Karuppagounder, Saravanan; Rohr, Jürgen; Ratan, Rajiv R.

2011-01-01

220

Microtubule-associated histone deacetylase 6 supports the calcium store sensor STIM1 in mediating malignant cell behaviors.  

PubMed

Stromal-interaction molecule 1 (STIM1) is an endoplasmic reticulum Ca(2+) storage sensor that promotes cell growth, migration, and angiogenesis in breast and cervical cancers. Here, we report that the microtubule-associated histone deacetylase 6 (HDAC6) differentially regulates activation of STIM1-mediated store-operated Ca(2+) entry (SOCE) between cervical cancer cells and normal cervical epithelial cells. Confocal microscopy of living cells indicated that microtubule integrity was necessary for STIM1 trafficking to the plasma membrane and interaction with Orai1, an essential pore subunit of SOCE. Cancer cells overexpressed both STIM1 and Orai1 compared with normal cervical epithelial cells. HDAC6 upregulation in cancer cells was accompanied by hypoacetylated ?-tubulin. Tubastatin-A, a specific HDAC6 inhibitor, inhibited STIM1 translocation to plasma membrane and blocked SOCE activation in cancer cells but not normal epithelial cells. Genetic or pharmacologic inhibition of HDAC6 blocked STIM1 membrane trafficking and downstream Ca(2+) influx, as evidenced by total internal reflection fluorescent images and intracellular Ca(2+) determination. In contrast, HDAC6 inhibition did not affect interactions between STIM1 and the microtubule plus end-binding protein EB1. Analysis of surgical specimens confirmed that most cervical cancer tissues overexpressed STIM1 and Orai1, accompanied by hypoacetylated ?-tubulin. Together, our results identify HDAC6 as a candidate target to disrupt STIM1-mediated SOCE as a general strategy to block malignant cell behavior. PMID:23698468

Chen, Ying-Ting; Chen, Yih-Fung; Chiu, Wen-Tai; Liu, Kuan-Yu; Liu, Yu-Lin; Chang, Jang-Yang; Chang, Hsien-Chang; Shen, Meng-Ru

2013-07-15

221

Inhibition of Class I Histone Deacetylases Unveils a Mitochondrial Signature and Enhances Oxidative Metabolism in Skeletal Muscle and Adipose Tissue  

PubMed Central

Chromatin modifications are sensitive to environmental and nutritional stimuli. Abnormalities in epigenetic regulation are associated with metabolic disorders such as obesity and diabetes that are often linked with defects in oxidative metabolism. Here, we evaluated the potential of class-specific synthetic inhibitors of histone deacetylases (HDACs), central chromatin-remodeling enzymes, to ameliorate metabolic dysfunction. Cultured myotubes and primary brown adipocytes treated with a class I–specific HDAC inhibitor showed higher expression of Pgc-1?, increased mitochondrial biogenesis, and augmented oxygen consumption. Treatment of obese diabetic mice with a class I– but not a class II–selective HDAC inhibitor enhanced oxidative metabolism in skeletal muscle and adipose tissue and promoted energy expenditure, thus reducing body weight and glucose and insulin levels. These effects can be ascribed to increased Pgc-1? action in skeletal muscle and enhanced PPAR?/PGC-1? signaling in adipose tissue. In vivo ChIP experiments indicated that inhibition of HDAC3 may account for the beneficial effect of the class I–selective HDAC inhibitor. These results suggest that class I HDAC inhibitors may provide a pharmacologic approach to treating type 2 diabetes. PMID:23069623

Galmozzi, Andrea; Mitro, Nico; Ferrari, Alessandra; Gers, Elise; Gilardi, Federica; Godio, Cristina; Cermenati, Gaia; Gualerzi, Alice; Donetti, Elena; Rotili, Dante; Valente, Sergio; Guerrini, Uliano; Caruso, Donatella; Mai, Antonello; Saez, Enrique; De Fabiani, Emma; Crestani, Maurizio

2013-01-01

222

Structure of Prokaryotic Polyamine Deacetylase Reveals Evolutionary Functional Relationships with Eukaryotic Histone Deacetylases  

SciTech Connect

Polyamines are a ubiquitous class of polycationic small molecules that can influence gene expression by binding to nucleic acids. Reversible polyamine acetylation regulates nucleic acid binding and is required for normal cell cycle progression and proliferation. Here, we report the structures of Mycoplana ramosa acetylpolyamine amidohydrolase (APAH) complexed with a transition state analogue and a hydroxamate inhibitor and an inactive mutant complexed with two acetylpolyamine substrates. The structure of APAH is the first of a histone deacetylase-like oligomer and reveals that an 18-residue insert in the L2 loop promotes dimerization and the formation of an 18 {angstrom} long 'L'-shaped active site tunnel at the dimer interface, accessible only to narrow and flexible substrates. The importance of dimerization for polyamine deacetylase function leads to the suggestion that a comparable dimeric or double-domain histone deacetylase could catalyze polyamine deacetylation reactions in eukaryotes.

P Lombardi; H Angell; D Whittington; E Flynn; K Rajashankar; D Christianson

2011-12-31

223

Carbocysteine restores steroid sensitivity by targeting histone deacetylase 2 in a thiol/GSH-dependent manner.  

PubMed

Steroid insensitivity is commonly observed in patients with chronic obstructive pulmonary disease. Here, we report the effects and mechanisms of carbocysteine (S-CMC), a mucolytic agent, in cellular and animal models of oxidative stress-mediated steroid insensitivity. The following results were obtained: oxidative stress induced higher levels of interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-?), which are insensitive to dexamethasone (DEX). The failure of DEX was improved by the addition of S-CMC by increasing histone deacetylase 2 (HDAC2) expression/activity. S-CMC also counteracted the oxidative stress-induced increase in reactive oxygen species (ROS) levels and decreases in glutathione (GSH) levels and superoxide dismutase (SOD) activity. Moreover, oxidative stress-induced events were decreased by the thiol-reducing agent dithiothreitol (DTT), enhanced by the thiol-oxidizing agent diamide, and the ability of DEX was strengthened by DTT. In addition, the oxidative stress-induced decrease in HDAC2 activity was counteracted by S-CMC by increasing thiol/GSH levels, which exhibited a direct interaction with HDAC2. S-CMC treatment increased HDAC2 recruitment and suppressed H4 acetylation of the IL-8 promoter, and this effect was further ablated by addition of buthionine sulfoximine, a specific inhibitor of GSH synthesis. Our results indicate that S-CMC restored steroid sensitivity by increasing HDAC2 expression/activity in a thiol/GSH-dependent manner and suggest that S-CMC may be useful in a combination therapy with glucocorticoids for treatment of steroid-insensitive pulmonary diseases. PMID:25500537

Song, Yun; Lu, Hao-Zhong; Xu, Jian-Rong; Wang, Xiao-Lin; Zhou, Wei; Hou, Li-Na; Zhu, Liang; Yu, Zhi-Hua; Chen, Hong-Zhuan; Cui, Yong-Yao

2015-01-01

224

Acute ?-adrenergic activation triggers nuclear import of histone deacetylase 5 and delays G(q)-induced transcriptional activation.  

PubMed

During hemodynamic stress, catecholamines and neurohumoral stimuli may induce co-activation of G(q)-coupled receptors and ?-adrenergic receptors (?-AR), leading to cardiac remodeling. Dynamic regulation of histone deacetylase 5 (HDAC5), a transcriptional repressor, is crucial during stress signaling due to its role in epigenetic control of fetal gene markers. Little is known about its regulation during acute and chronic ?-AR stimulation and its cross-interaction with G(q) signaling in adult cardiac myocytes. Here, we evaluate the potential cross-talk between G(q)-driven and ?-AR mediated signaling at the level of nucleocytoplasmic shuttling of HDAC5. We show the translocation of GFP-tagged wild type HDAC5 or mutants (S279A and S279D) in response to ?-AR or G(q) agonists. Isoproterenol (ISO) or PKA activation results in strong nuclear accumulation of HDAC5 in contrast to nuclear export driven by Ca(2+)-calmodulin protein kinase II and protein kinase D. Moreover, nuclear accumulation of HDAC5 under acute ISO/PKA signaling is dependent on phosphorylation of Ser-279 and can block subsequent G(q)-mediated nuclear HDAC5 export. Intriguingly, the attenuation of G(q)-induced export is abolished after chronic PKA activation, yet nuclear HDAC5 remains elevated. Last, the effect of chronic ?-AR signaling on HDAC5 translocation was examined in adult myocytes from a rabbit model of heart failure, where ISO-induced nuclear import is ablated, but G(q)-agonist mediated export is preserved. Acute ?-AR/PKA activation protects against hypertrophic signaling by delaying G(q)-mediated transcriptional activation. This serves as a key physiological control switch before allowing genetic reprogramming via HDAC5 nuclear export during more severe stress, such as heart failure. PMID:23161540

Chang, Chia-Wei Jenny; Lee, Linda; Yu, David; Dao, Khanha; Bossuyt, Julie; Bers, Donald M

2013-01-01

225

Probing the elusive catalytic activity of vertebrate class IIa histone deacetylases.  

PubMed

It has been widely debated whether class IIa HDACs have catalytic deacetylase activity, and whether this plays any part in controlling gene expression. Herein, it has been demonstrated that class IIa HDACs isolated from mammalian cells are contaminated with other deacetylases, but can be prepared cleanly in Escherichia coli. These bacteria preparations have weak but measurable deacetylase activity. The low efficiency can be restored either by: mutation of an active site histidine to tyrosine, or by the use of a non-acetylated lysine substrate, allowing the development of assays to identify class IIa HDAC inhibitors. PMID:18308563

Jones, Philip; Altamura, Sergio; De Francesco, Raffaele; Gallinari, Paola; Lahm, Armin; Neddermann, Petra; Rowley, Michael; Serafini, Sergio; Steinkühler, Christian

2008-03-15

226

Pitx2-dependent Occupancy by Histone Deacetylases Is Associated with T-box Gene Regulation in Mammalian Abdominal Tissue*?  

PubMed Central

The homeodomain transcription factor Pitx2 and the T-box transcription factors are essential for organogenesis. Pitx2 and T-box genes are induced by growth factors and function as transcriptional activators or repressors. Gene expression analyses on abdominal tissue were used to identify seven of the T-box genes of the genome as Pitx2 target genes in the abdomen at embryonic day.10.5. Pitx2 activated Tbx4, Tbx15, and Mga and repressed Tbx1, Tbx2, Tbx5, and Tbx6 expression. As expected, activated genes showed reduced expression patterns, and repressed T-box genes showed increased expression patterns in the abdomen of Pitx2 mutants. Pitx2 occupied chromatin sites near all of these T-box genes. Co-occupancy by coactivators, corepressors, and histone acetylation at these sites was frequently Pitx2-dependent. Genes repressed by Pitx2 generally showed increased histone acetylation and decreased histone deacetylase (HDAC)/corepressor occupancy in Pitx2 mutants. The lower N-CoR, HDAC1, and HDAC3 occupancy observed at multiple sites along Tbx1 chromatin in mutants is consistent with the model that increased histone acetylation and gene expression of Tbx1 may result from a loss of recruitment of corepressors by Pitx2. Genes activated by Pitx2 showed less consistent patterns in chromatin analyses. Reduced H4 acetylation and increased HDAC1/nuclear receptor corepressor (N-CoR) occupancy at some Tbx4 sites were accompanied by increased H3 acetylation and reduced HDAC3 occupancy at the same or other more distal chromatin sites in mutants. Pitx2-dependent occupancy by corepressors resulted in alteration of the acetylation levels of several T-box genes, whereas Pitx2-dependent occupancy by coactivators was more site-localized. These studies will provide the basic scientific underpinning to understand abdominal wall syndromes. PMID:20129917

Hilton, Traci; Gross, Michael K.; Kioussi, Chrissa

2010-01-01

227

Overview of Histone Deacetylase Inhibitors in Haematological Malignancies  

PubMed Central

Histone deacetylase inhibitors (HDACi) can induce hyperacetylation of both histone and non-histone target resulting in epigenetic reprogramming and altered activity, stability and localisation of non-histone proteins to ultimately mediate diverse biological effects on cancer cells and their microenvironment. Clinical trials have demonstrated single agent HDACi to have activity in hematological malignancies, in particular T-cell lymphoma and Hodgkin lymphoma. Combination strategies with standard therapies based on pre-clinical data are being employed with significant success due to their excellent side effect profile. Correlative studies will provide valuable information on the sub-groups of patients more likely to respond or be resistant to HDACi therapy, while long-term monitoring for toxicities is also needed.

Bishton, Mark J.; Johnstone, Ricky W.; Dickinson, Michael; Harrison, Simon; Prince, H. Miles

2010-01-01

228

Mechanisms of G1 cell cycle arrest and apoptosis in myeloma cells induced by hybrid-compound histone deacetylase inhibitor  

SciTech Connect

Highlights: •Novel histone deacetylase inhibitor Ky-2, remarkably inhibits myeloma cell growth. •Ky-2 demonstrates no cytotoxicity against normal lymphocytic cells. •Ky-2 induces cell cycle arrest through the cell cycle-associated proteins. •Ky-2 induces Bcl-2-inhibitable apoptosis through a caspase-dependent cascade. -- Abstract: Objectives: Histone deacetylase (HDAC) inhibitors are new therapeutic agents, used to treat various types of malignant cancers. In the present study, we investigated the effects of Ky-2, a hybrid-compound HDAC inhibitor, on the growth of mouse myeloma cells. Materials and methods: Myeloma cells, HS-72, P3U1, and mouse normal cells were used in this study. Effect of HDAC inhibitors on cell viability was determined by WST-assay and trypan blue assay. Cell cycle was analyzed using flow cytometer. The expression of cell cycle regulatory and the apoptosis associated proteins were examined by Western blot analysis. Hoechst’s staining was used to detect apoptotic cells. Results: Our findings showed that Ky-2 decreased the levels of HDACs, while it enhanced acetylation of histone H3. Myeloma cell proliferation was inhibited by Ky-2 treatment. Interestingly, Ky-2 had no cytotoxic effects on mouse normal cells. Ky-2 treatment induced G1-phase cell cycle arrest and accumulation of a sub-G1 phase population, while Western blotting analysis revealed that expressions of the cell cycle-associated proteins were up-regulated. Also, Ky-2 enhanced the cleavage of caspase-9 and -3 in myeloma cells, followed by DNA fragmentation. In addition, Ky-2 was not found to induce apoptosis in bcl-2 overexpressing myeloma cells. Conclusion: These findings suggest that Ky-2 induces apoptosis via a caspase-dependent cascade and Bcl-2-inhibitable mechanism in myeloma cells.

Fujii, Seiko [Division of Infections and Molecular Biology, Kyushu Dental University (Japan) [Division of Infections and Molecular Biology, Kyushu Dental University (Japan); Division of Maxillofacial Surgery, Kyushu Dental University (Japan); Okinaga, Toshinori; Ariyoshi, Wataru [Division of Infections and Molecular Biology, Kyushu Dental University (Japan) [Division of Infections and Molecular Biology, Kyushu Dental University (Japan); Oral Biology Research Center, Kyushu Dental University (Japan); Takahashi, Osamu; Iwanaga, Kenjiro [Division of Maxillofacial Surgery, Kyushu Dental University (Japan)] [Division of Maxillofacial Surgery, Kyushu Dental University (Japan); Nishino, Norikazu [Oral Biology Research Center, Kyushu Dental University (Japan)] [Oral Biology Research Center, Kyushu Dental University (Japan); Tominaga, Kazuhiro [Division of Maxillofacial Surgery, Kyushu Dental University (Japan)] [Division of Maxillofacial Surgery, Kyushu Dental University (Japan); Nishihara, Tatsuji, E-mail: tatsujin@kyu-dent.ac.jp [Division of Infections and Molecular Biology, Kyushu Dental University (Japan) [Division of Infections and Molecular Biology, Kyushu Dental University (Japan); Oral Biology Research Center, Kyushu Dental University (Japan)

2013-05-10

229

Apoptosis Induced by the Histone Deacetylase Inhibitor FR901228 in Human T-Cell Leukemia Virus Type 1Infected T-Cell Lines and Primary Adult T-Cell Leukemia Cells  

Microsoft Academic Search

Inhibition of histone deacetylase (HDAC) activity induces growth arrest, differentiation, and, in certain cell types, apoptosis. FR901228, FK228, or depsipeptide, is an HDAC inhibitor effective in T-cell lymphomas. Adult T-cell leukemia (ATL) is caused by human T-cell leukemia virus type 1 (HTLV-1) and remains incurable. We examined whether FR901228 is effective for treatment of ATL by assessing its ability to

Naoki Mori; Takehiro Matsuda; Masayuki Tadano; Takao Kinjo; Yasuaki Yamada; Kunihiro Tsukasaki; Shuichi Ikeda; Yoshihiro Yamasaki; Yuetsu Tanaka; Takao Ohta; Teruo Iwamasa; Masao Tomonaga; Naoki Yamamoto

2004-01-01

230

Phase II Study of the Histone Deacetylase Inhibitor MGCD0103 in Patients with Previously Treated Chronic Lymphocytic Leukemia  

PubMed Central

MGCD0103, an orally available class I histone deacetylase (HDAC) inhibitor, was examined for pre-clinical activity in chronic lymphocytic leukaemia (CLL). A phase II clinical trial was performed, starting at a dose of 85 mg/day, three times per week. Dose escalation to 110 mg or the addition of rituximab was permitted in patients without a response after 2 or more cycles. MGCD0103 demonstrated pre-clinical activity against CLL cells with a LC50 (concentration lethal to 50%) of 0.23 ?M and increased acetylation of the HDAC class I specific target histone H3. Twenty-one patients received a median of 2 cycles of MGCD0103 (range, 0–12). All patients had previously received fludarabine, 33% were fludarabine refractory, and 71% had del(11q22.3) or del(17p13.1). No responses according to the National Cancer Institutes 1996 criteria were observed. Three patients received 110 mg and 4 patients received concomitant rituximab, with no improvement in response. Grade 3–4 toxicity consisted of infections, thrombocytopenia, anemia, diarrhea, and fatigue. HDAC inhibition was observed in 6 out of 9 patients on day 8. Limited activity was observed with single agent MGCD0103 in high risk patients with CLL. Future investigations in CLL should focus on broad HDAC inhibition, combination strategies, and approaches to diminish constitutional symptoms associated with this class of drugs. PMID:19747365

Blum, Kristie A.; Advani, Anjani; Fernandez, Louis; Van Der Jagt, Richard; Brandwein, Joseph; Kambhampati, Suman; Kassis, Jeannine; Davis, Melanie; Bonfils, Claire; Dubay, Marja; Dumouchel, Julie; Drouin, Michel; Lucas, David M.; Martell, Robert E.; Byrd, John C.

2009-01-01

231

Histone deacetylase regulates high mobility group A2-targeting microRNAs in human cord blood-derived multipotent stem cell aging  

Microsoft Academic Search

Cellular senescence involves a reduction in adult stem cell self-renewal, and epigenetic regulation of gene expression is\\u000a one of the main underlying mechanisms. Here, we observed that the cellular senescence of human umbilical cord blood-derived\\u000a multipotent stem cells (hUCB-MSCs) caused by inhibition of histone deacetylase (HDAC) activity leads to down-regulation of\\u000a high mobility group A2 (HMGA2) and, on the contrary,

Seunghee Lee; Ji-Won Jung; Sang-Bum Park; Kyounghwan Roh; Su Yeon Lee; Ju Han Kim; Soo-Kyung Kang; Kyung-Sun Kang

2011-01-01

232

Inhibition of Histone Deacetylase Activity in Human Endometrial Stromal Cells Promotes Extracellular Matrix Remodelling and Limits Embryo Invasion  

PubMed Central

Invasion of the trophoblast into the maternal decidua is regulated by both the trophoectoderm and the endometrial stroma, and entails the action of tissue remodeling enzymes. Trophoblast invasion requires the action of metalloproteinases (MMPs) to degrade extracellular matrix (ECM) proteins and in turn, decidual cells express tissue inhibitors of MMPs (TIMPs). The balance between these promoting and restraining factors is a key event for the successful outcome of pregnancy. Gene expression is post-transcriptionally regulated by histone deacetylases (HDACs) that unpacks condensed chromatin activating gene expression. In this study we analyze the effect of histone acetylation on the expression of tissue remodeling enzymes and activity of human endometrial stromal cells (hESCs) related to trophoblast invasion control. Treatment of hESCs with the HDAC inhibitor trichostatin A (TSA) increased the expression of TIMP-1 and TIMP-3 while decreased MMP-2, MMP-9 and uPA and have an inhibitory effect on trophoblast invasion. Moreover, histone acetylation is detected at the promoters of TIMP-1 and TIMP-3 genes in TSA-treated. In addition, in an in vitro decidualized hESCs model, the increase of TIMP-1 and TIMP-3 expression is associated with histone acetylation at the promoters of these genes. Our results demonstrate that histone acetylation disrupt the balance of ECM modulators provoking a restrain of trophoblast invasion. These findings are important as an epigenetic mechanism that can be used to control trophoblast invasion. PMID:22291969

Atkinson, Stuart P.; Quiñonero, Alicia; Martínez, Sebastián; Pellicer, Antonio; Simón, Carlos

2012-01-01

233

Clinical Toxicities of Histone Deacetylase Inhibitors  

PubMed Central

The HDAC inhibitors are a new family of antineoplastic agents. Since the entry of these agents into our therapeutic armamentarium, there has been increasing interest in their use. Although this family comprises chemical compounds from unrelated chemical classes that have different HDAC isoform specificities, they surprisingly have very similar toxicity profiles. In contrast, the observed toxicity profile is somewhat different from that of traditional cytotoxic chemotherapeutic agents and from other epigenetic agents. While some of the side effects may be familiar to the oncologist, others are less commonly seen. As some patients remain on therapy for a prolonged period of time, the long-term sequelae need to be characterized. In addition, since preclinical models suggest promising activity when used in combination with other antineoplastic agents, combination trials are being pursued. It will thus be important to distinguish the relative toxicity attributed to these agents and be alert to the exacerbation of toxicities observed in single agent studies. Notably, few of the agents in this class have completed phase 2 testing. Consequently, more clinical experience is needed to determine the relative frequency of the observed side effects, and to identify and develop approaches to mitigate potential clinical sequelae.

Subramanian, Srividya; Bates, Susan E.; Wright, John J.; Espinoza-Delgado, Igor; Piekarz, Richard L.

2010-01-01

234

Rapid changes in histone deacetylases and inflammatory gene expression in expert meditators  

PubMed Central

BACKGROUND A growing body of research shows that mindfulness meditation can alter neural, behavioral and biochemical processes. However, the mechanisms responsible for such clinically relevant effects remain elusive. METHODS Here we explored the impact of a day of intensive practice of mindfulness meditation in experienced subjects (n= 19) on the expression of circadian, chromatin modulatory and inflammatory genes in peripheral blood mononuclear cells (PBMCs). In parallel, we analyzed a control group of subjects with no meditation experience who engaged in leisure activities in the same environment (n= 21). PBMCs from all participants were obtained before (t1) and after (t2) the intervention (t2-t1= 8 hours) and gene expression was analyzed using custom pathway focused quantitative-real time PCR assays. Both groups were also presented with the Trier Social Stress Test (TSST). RESULTS Core clock gene expression at baseline (t1) was similar between groups and their rhythmicity was not influenced in meditators by the intensive day of practice. Similarly, we found that all the epigenetic regulatory enzymes and inflammatory genes analyzed exhibited similar basal expression levels in the two groups. In contrast, after the brief intervention we detected reduced expression of histone deacetylase genes (HDAC2, 3 and 9), alterations in global modification of histones (H4ac; H3K4me3) and decreased expression of pro-inflammatory genes (RIPK2 and COX2) in meditators compared with controls. We found that the expression of RIPK2 and HDAC2 genes was associated with a faster cortisol recovery to the TSST in both groups. CONCLUSIONS The regulation of HDACs and inflammatory pathways may represent some of the mechanisms underlying the therapeutic potential of mindfulness-based interventions. Our findings set the foundation for future studies to further assess meditation strategies for the treatment of chronic inflammatory conditions. PMID:24485481

Kaliman, Perla; Álvarez-López, María Jesús; Cosín-Tomás, Marta; Rosenkranz, Melissa A.; Lutz, Antoine; Davidson, Richard J.

2013-01-01

235

A histone deacetylase inhibitor improves hypothyroidism caused by a TR?1 mutant.  

PubMed

Mutations of the thyroid hormone receptor ? gene (THRA) cause hypothyroidism in patients with growth and developmental retardation, and skeletal dysplasia. Genetic evidence indicates that the dominant negative activity of TR?1 mutants underlies pathological manifestations. Using a mouse model of hypothyroidism caused by a dominant negative TR?1PV mutant and its derived mouse model harboring a mutated nuclear receptor corepressor (NCOR1?ID) (Thra1(PV/+)Ncor1(?ID/?ID) mice), we recently showed that aberrant release of TR?1 mutants from the NCOR1 repressor complex mediates dominant negative actions of TR?1 mutants in vivo. We tested the hypothesis that deacetylation of nucleosomal histones associated with aberrant recruitment of corepressors by TR?1 mutants underlies pathological phenotypic expression. We treated Thra1(PV/+)and Thra1(PV/+)Ncor1(?ID/?ID) mice with a histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxyamic acid (SAHA). SAHA significantly ameliorated the impaired growth, bone development and adipogenesis of Thra1(PV/+) mice. In Thra1(PV/+)Ncor1(?ID/?ID) mice, SAHA improved these abnormalities even further. We focused our molecular analyses on how SAHA improved the impaired adipogenesis leading to the lean phenotype. We found that SAHA reverted the impaired adipogenesis by de-repressing the expression of the two master regulators of adipogenesis, C/ebp? and Ppar?, as well as other adipogenic genes at both the mRNA and protein levels. Chromatin immunoprecipitation analyses indicated SAHA increased the extent of acetylation of nucleosomal H4K5 and H3 to re-activate adipogenic genes to reverting adipogenesis. Thus, HDAC confers in vivo aberrant actions of TR?1 mutants. Importantly, for the first time, the present studies show that HDAC inhibitors are clearly beneficial for hypothyroidism and could be therapeutics for treatment. PMID:24381310

Kim, Dong Wook; Park, Jeong Won; Willingham, Mark C; Cheng, Sheue-yann

2014-05-15

236

Histone deacetylase inhibitors are potent inducers of gene expression in latent EBV and sensitize lymphoma cells to nucleoside antiviral agents.  

PubMed

Induction of EBV lytic-phase gene expression, combined with exposure to an antiherpes viral drug, represents a promising targeted therapeutic approach to EBV-associated lymphomas. Short-chain fatty acids or certain chemotherapeutics have been used to induce EBV lytic-phase gene expression in cultured cells and mouse models, but these studies generally have not translated into clinical application. The recent success of a clinical trial with the pan-histone deacetylase (pan-HDAC) inhibitor arginine butyrate and the antiherpes viral drug ganciclovir in the treatment of EBV lymphomas prompted us to investigate the potential of several HDAC inhibitors, including some new, highly potent compounds, to sensitize EBV(+) human lymphoma cells to antiviral agents in vitro. Our study included short-chain fatty acids (sodium butyrate and valproic acid); hydroxamic acids (oxamflatin, Scriptaid, suberoyl anilide hydroxamic acid, panobinostat [LBH589], and belinostat [PXD101]); the benzamide MS275; the cyclic tetrapeptide apicidin; and the recently discovered HDAC inhibitor largazole. With the exception of suberoyl anilide hydroxamic acid and PXD101, all of the other HDAC inhibitors effectively sensitized EBV(+) lymphoma cells to ganciclovir. LBH589, MS275, and largazole were effective at nanomolar concentrations and were 10(4) to 10(5) times more potent than butyrate. The effectiveness and potency of these HDAC inhibitors make them potentially applicable as sensitizers to antivirals for the treatment of EBV-associated lymphomas. PMID:22160379

Ghosh, Sajal K; Perrine, Susan P; Williams, Robert M; Faller, Douglas V

2012-01-26

237

Histone deacetylase inhibition increases levels of choline kinase alpha and phosphocholine facilitating non-invasive imaging in human cancers  

PubMed Central

Histone deacetylase (HDAC) inhibitors are currently approved for cutaneous T-cell lymphoma and are in mid-late stage trials for other cancers. The HDAC inhibitors LAQ824 and SAHA increase phosphocholine (PC) levels in human colon cancer cells and tumor xenografts as observed by magnetic resonance spectroscopy (MRS). In this study, we show that belinostat, an HDAC inhibitor with an alternative chemical scaffold, also caused a rise in cellular PC content that was detectable by 1H and 31P MRS in prostate and colon carcinoma cells. In addition, 1H MRS showed an increase in branched chain amino acid and alanine concentrations. 13C-choline labeling indicated that the rise in PC resulted from increased de novo synthesis and correlated with an induction of choline kinase ? (ChoK?) expression. Furthermore, metabolic labeling experiments with 13C-glucose showed that differential glucose routing favored alanine formation at the expense of lactate production. Additional analysis revealed increases in the choline/water and phosphomonoester (including PC)/total phosphate ratios in vivo. Together, our findings provide mechanistic insights into the impact of HDAC inhibition on cancer cell metabolism and highlight PC as a candidate non-invasive imaging biomarker for monitoring the action of HDAC inhibitors. PMID:22194463

Beloueche-Babari, Mounia; Arunan, Vaitha; Troy, Helen; te Poele, Robert H; Fong, Anne-Christine Wong Te; Jackson, L Elizabeth; Payne, Geoffrey S; Griffiths, John R; Judson, Ian R; Workman, Paul; Leach, Martin O; Chung, Yuen-Li

2012-01-01

238

Highly active combination of BRD4 antagonist and histone deacetylase inhibitor against human acute myelogenous leukemia cells.  

PubMed

The bromodomain and extra-terminal (BET) protein family members, including BRD4, bind to acetylated lysines on histones and regulate the expression of important oncogenes, for example, c-MYC and BCL2. Here, we demonstrate the sensitizing effects of the histone hyperacetylation-inducing pan-histone deacetylase (HDAC) inhibitor panobinostat on human acute myelogenous leukemia (AML) blast progenitor cells (BPC) to the BET protein antagonist JQ1. Treatment with JQ1, but not its inactive enantiomer (R-JQ1), was highly lethal against AML BPCs expressing mutant NPM1c+ with or without coexpression of FLT3-ITD or AML expressing mixed lineage leukemia fusion oncoprotein. JQ1 treatment reduced binding of BRD4 and RNA polymerase II to the DNA of c-MYC and BCL2 and reduced their levels in the AML cells. Cotreatment with JQ1 and the HDAC inhibitor panobinostat synergistically induced apoptosis of the AML BPCs, but not of normal CD34(+) hematopoietic progenitor cells. This was associated with greater attenuation of c-MYC and BCL2, while increasing p21, BIM, and cleaved PARP levels in the AML BPCs. Cotreatment with JQ1 and panobinostat significantly improved the survival of the NOD/SCID mice engrafted with OCI-AML3 or MOLM13 cells (P < 0.01). These findings highlight cotreatment with a BRD4 antagonist and an HDAC inhibitor as a potentially efficacious therapy of AML. PMID:24435446

Fiskus, Warren; Sharma, Sunil; Qi, Jun; Valenta, John A; Schaub, Leasha J; Shah, Bhavin; Peth, Karissa; Portier, Bryce P; Rodriguez, Melissa; Devaraj, Santhana G T; Zhan, Ming; Sheng, Jianting; Iyer, Swaminathan P; Bradner, James E; Bhalla, Kapil N

2014-05-01

239

Treatment of Niemann--pick type C disease by histone deacetylase inhibitors.  

PubMed

Niemann-Pick type C disease (NPC) is a devastating, recessive, inherited disorder that causes accumulation of cholesterol and other lipids in late endosomes and lysosomes. Mutations in 2 genes, NPC1 and NPC2, are responsible for the disease, which affects about 1 in 120,000 live births. About 95% of patients have mutations in NPC1, a large polytopic membrane protein that is normally found in late endosomes. More than 200 missense mutations in NPC1 have been found in NPC patients. The disease is progressive, typically leading to death before the age of 20 years, although some affected individuals live well into adulthood. The disease affects peripheral organs, including the liver, spleen, and lungs, but the most severe symptoms are associated with neurological disease. There are some palliative treatments that slow progression of NPC disease. Recently, it was found that histone deacetylase (HDAC) inhibitors that are effective against HDACs 1, 2, and 3 can reduce the cholesterol accumulation in fibroblasts derived from NPC patients with mutations in NPC1. One example is vorinostat. As vorinostat is a Food and Drug Administration-approved drug for treatment of cutaneous T-cell lymphoma, this opens up the possibility that HDAC inhibitors could be repurposed for treatment of this rare disease. The mechanism of action of the HDAC inhibitors requires further study, but these drugs increase the level of the NPC1 protein. This may be due to post-translational stabilization of the NPC1 protein, allowing it to be transported out of the endoplasmic reticulum. PMID:24048860

Helquist, Paul; Maxfield, Frederick R; Wiech, Norbert L; Wiest, Olaf

2013-10-01

240

Analysis of the genomic response of human prostate cancer cells to histone deacetylase inhibitors  

PubMed Central

Histone deacetylases (HDACs) have emerged as important targets for cancer treatment. HDAC-inhibitors (HDACis) are well tolerated in patients and have been approved for the treatment of patients with cutaneous T-cell lymphoma (CTCL). To improve the clinical benefit of HDACis in solid tumors, combination strategies with HDACis could be employed. In this study, we applied Analysis of Functional Annotation (AFA) to provide a comprehensive list of genes and pathways affected upon HDACi-treatment in prostate cancer cells. This approach provides an unbiased and objective approach to high throughput data mining. By performing AFA on gene expression data from prostate cancer cell lines DU-145 (an HDACi-sensitive cell line) and PC3 (a relatively HDACi-resistant cell line) treated with HDACis valproic acid or vorinostat, we identified biological processes that are affected by HDACis and are therefore potential treatment targets for combination therapy. Our analysis revealed that HDAC-inhibition resulted among others in upregulation of major histocompatibility complex (MHC) genes and deregulation of the mitotic spindle checkpoint by downregulation of genes involved in mitosis. These findings were confirmed by AFA on publicly available data sets from HDACi-treated prostate cancer cells. In total, we analyzed 375 microarrays with HDACi treated and non-treated (control) prostate cancer cells. All results from this extensive analysis are provided as an online research source (available at the journal’s website and at http://luigimarchionni.org/HDACIs.html). By publishing this data, we aim to enhance our understanding of the cellular changes after HDAC-inhibition, and to identify novel potential combination strategies with HDACis for the treatment of prostate cancer patients. PMID:23880963

Kortenhorst, Madeleine SQ; Wissing, Michel D; Rodriguez, Ronald; Kachhap, Sushant K; Jans, Judith JM; Van der Groep, Petra; Verheul, Henk MW; Gupta, Anuj; Aiyetan, Paul O; van der Wall, Elsken; Carducci, Michael A; Van Diest, Paul J; Marchionni, Luigi

2013-01-01

241

Structural studies of human histone deacetylase 8 and its site-specific variants complexed with substrate and inhibitors.  

PubMed

Metal-dependent histone deacetylases (HDACs) require Zn(2+) or Fe(2+) to regulate the acetylation of lysine residues in histones and other proteins in eukaryotic cells. Isozyme HDAC8 is perhaps the archetypical member of the class I HDAC family and serves as a paradigm for studying structure-function relationships. Here, we report the structures of HDAC8 complexes with trichostatin A and 3-(1-methyl-4-phenylacetyl-1H-2-pyrrolyl)-N-hydroxy-2-propenamide (APHA) in a new crystal form. The structure of the APHA complex reveals that the hydroxamate CO group accepts a hydrogen bond from Y306 but does not coordinate to Zn(2+) with favorable geometry, perhaps due to the constraints of its extended pi system. Additionally, since APHA binds to only two of the three protein molecules in the asymmetric unit of this complex, the structure of the third monomer represents the first structure of HDAC8 in the unliganded state. Comparison of unliganded and liganded structures illustrates ligand-induced conformational changes in the L2 loop that likely accompany substrate binding and catalysis. Furthermore, these structures, along with those of the D101N, D101E, D101A, and D101L variants, support the proposal that D101 is critical for the function of the L2 loop. However, amino acid substitutions for D101 can also trigger conformational changes of Y111 and W141 that perturb the substrate binding site. Finally, the structure of H143A HDAC8 complexed with an intact acetylated tetrapeptide substrate molecule confirms the importance of D101 for substrate binding and reveals how Y306 and the active site zinc ion together bind and activate the scissile amide linkage of acetyllysine. PMID:19053282

Dowling, Daniel P; Gantt, Stephanie L; Gattis, Samuel G; Fierke, Carol A; Christianson, David W

2008-12-23

242

Structural Studies of Human Histone Deacetylase 8 and Its Site-Specific Variants Complexed with Substrate and Inhibitors  

SciTech Connect

Metal-dependent histone deacetylases (HDACs) require Zn2+ or Fe2+ to regulate the acetylation of lysine residues in histones and other proteins in eukaryotic cells. Isozyme HDAC8 is perhaps the archetypical member of the class I HDAC family and serves as a paradigm for studying structure-function relationships. Here, we report the structures of HDAC8 complexes with trichostatin A and 3-(1-methyl-4-phenylacetyl-1H-2-pyrrolyl)-N-hydroxy-2-propenamide (APHA) in a new crystal form. The structure of the APHA complex reveals that the hydroxamate CO group accepts a hydrogen bond from Y306 but does not coordinate to Zn2+ with favorable geometry, perhaps due to the constraints of its extended ? system. Additionally, since APHA binds to only two of the three protein molecules in the asymmetric unit of this complex, the structure of the third monomer represents the first structure of HDAC8 in the unliganded state. Comparison of unliganded and liganded structures illustrates ligand-induced conformational changes in the L2 loop that likely accompany substrate binding and catalysis. Furthermore, these structures, along with those of the D101N, D101E, D101A, and D101L variants, support the proposal that D101 is critical for the function of the L2 loop. However, amino acid substitutions for D101 can also trigger conformational changes of Y111 and W141 that perturb the substrate binding site. Finally, the structure of H143A HDAC8 complexed with an intact acetylated tetrapeptide substrate molecule confirms the importance of D101 for substrate binding and reveals how Y306 and the active site zinc ion together bind and activate the scissile amide linkage of acetyllysine.

Dowling, D.; Gantt, S; Gattis, S; Fierke, C; Christianson, D

2008-01-01

243

Effect of histone deacetylase inhibitors trichostatin A and valproic acid on hair cell regeneration in zebrafish lateral line neuromasts  

PubMed Central

In humans, auditory hair cells are not replaced when injured. Thus, cochlear hair cell loss causes progressive and permanent hearing loss. Conversely, non-mammalian vertebrates are capable of regenerating lost sensory hair cells. The zebrafish lateral line has numerous qualities that make it well-suited for studying hair cell development and regeneration. Histone deacetylase (HDAC) activity has been shown to have an important role in regenerative processes in vertebrates, but its function in hair cell regeneration in vivo is not fully understood. Here, we have examined the role of HDAC activity in hair cell regeneration in the zebrafish lateral line. We eliminated lateral line hair cells of 5-day post-fertilization larvae using neomycin and then treated the larvae with HDAC inhibitors. To assess hair cell regeneration, we used 5-bromo-2-deoxyuridine (BrdU) incorporation in zebrafish larvae to label mitotic cells after hair cell loss. We found that pharmacological inhibition of HDACs using trichostatin A (TSA) or valproic acid (VPA) increased histone acetylation in the regenerated neuromasts following neomycin-induced damage. We also showed that treatment with TSA or VPA decreased the number of supporting cells and regenerated hair cells in response to hair cell damage. Additionally, BrdU immunostaining and western blot analysis showed that TSA or VPA treatment caused a significant decrease in the percentage of S-phase cells and induced p21Cip1 and p27Kip1 expression, both of which are likely to explain the decrease in the amount of newly regenerated hair cells in treated embryos. Finally, we showed that HDAC inhibitors induced no observable cell death in neuromasts as measured by cleaved caspase-3 immunohistochemistry and western blot analysis. Taken together, our results demonstrate that HDAC activity has an important role in the regeneration of hair cells in the lateral line. PMID:25431550

He, Yingzi; Cai, Chengfu; Tang, Dongmei; Sun, Shan; Li, Huawei

2014-01-01

244

Liganded Peroxisome Proliferator-Activated Receptors (PPARs) Preserve Nuclear Histone Deacetylase 5 Levels in Endothelin-Treated Sprague-Dawley Rat Cardiac Myocytes  

PubMed Central

Ligand activation of peroxisome proliferator-activated receptors (PPARs) prevents cardiac myocyte hypertrophy, and we previously reported that diacylglycerol kinase zeta (DGK?) is critically involved. DGK? is an intracellular lipid kinase that catalyzes phosphorylation of diacylglycerol; by attenuating DAG signaling, DGK? suppresses protein kinase C (PKC) and G-protein signaling. Here, we investigated how PPAR-DGK? signaling blocks activation of the hypertrophic gene program. We focused on export of histone deacetylase 5 (HDAC5) from the nucleus, a key event during hypertrophy, since crosstalk occurs between PPARs and other members of the HDAC family. Using cardiac myocytes isolated from Sprague-Dawley rats, we determined that liganded PPARs disrupt endothelin-1 (ET1)-induced nuclear export of HDAC5 in a manner that is dependent on DGK?. When DGK?-mediated PKC inhibition was circumvented using a constitutively-active PKC? mutant, PPARs failed to block ET1-induced nuclear retention of HDAC5. Liganded PPARs also prevented (i) activation of protein kinase D (the downstream effector of PKC), (ii) HDAC5 phosphorylation at 14-3-3 protein chaperone binding sites (serines 259 and 498), and (iii) physical interaction between HDAC5 and 14-3-3, all of which are consistent with blockade of nucleo-cytoplasmic shuttling of HDAC5. Finally, the ability of PPARs to prevent neutralization of HDAC5 activity was associated with transcriptional repression of hypertrophic genes. This occurred by first, reduced MEF2 transcriptional activity and second, augmented deacetylation of histone H3 associated with hypertrophic genes expressing brain natriuretic peptide, ?-myosin heavy chain, skeletal muscle ?-actin, and cardiac muscle ?-actin. Our findings identify spatial regulation of HDAC5 as a target for liganded PPARs, and to our knowledge, are the first to describe a mechanistic role for nuclear DGK? in cardiac myocytes. In conclusion, these results implicate modulation of HDAC5 as a mechanism by which liganded PPARs suppress the hypertrophic gene program. PMID:25514029

Zhang, Haining; Shao, Zongjun; Alibin, Caroline P.; Acosta, Crystal; Anderson, Hope D.

2014-01-01

245

Modulation of gamma globin genes expression by histone deacetylase inhibitors: an in vitro study.  

PubMed

Induction of fetal haemoglobin (HbF) is a promising therapeutic approach for the treatment of ?-thalassaemia and sickle cell disease (SCD). Several pharmacological agents, such as hydroxycarbamide (HC) and butyrates, have been shown to induce the ?-globin genes (HBG1, HBG2). However, their therapeutic use is limited due to weak efficacy and an inhibitory effect on erythroid differentiation. Thus, more effective agents are needed. The histone deacetylase (HDAC) inhibitors are potential therapeutic haemoglobin (Hb) inducers able to modulate gene expression through pleiotropic mechanisms. We investigated the effects of a HDAC inhibitor, Givinostat (GVS), on erythropoiesis and haemoglobin synthesis and compared it with sodium butyrate and HC. We used an in vitro erythropoiesis model derived from peripheral CD34? cells of healthy volunteers and SCD donors. GVS effects on erythroid proliferation and differentiation and on Hb synthesis were investigated. We found that GVS at high concentrations delayed erythroid differentiation with no specific effect on HBG1/2 transcription. At a low concentration (1 nmol/l), GVS induced Hb production with no effects on cells proliferation and differentiation. The efficacy of GVS 1 mol/l in Hb induction in vitro was comparable to that of HC and butyrate. Our results support the evaluation of GVS as a new candidate molecule for the treatment of the haemoglobinophathies due to its positive effects on haemoglobin production at low and non-toxic concentrations. PMID:24606390

Ronzoni, Luisa; Sonzogni, Laura; Fossati, Gianluca; Modena, Daniela; Trombetta, Elena; Porretti, Laura; Cappellini, Maria Domenica

2014-06-01

246

Role of autophagy in histone deacetylase inhibitor-induced apoptotic and nonapoptotic cell death  

PubMed Central

Autophagy is a cellular catabolic pathway by which long-lived proteins and damaged organelles are targeted for degradation. Activation of autophagy enhances cellular tolerance to various stresses. Recent studies indicate that a class of anticancer agents, histone deacetylase (HDAC) inhibitors, can induce autophagy. One of the HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA), is currently being used for treating cutaneous T-cell lymphoma and under clinical trials for multiple other cancer types, including glioblastoma. Here, we show that SAHA increases the expression of the autophagic factor LC3, and inhibits the nutrient-sensing kinase mammalian target of rapamycin (mTOR). The inactivation of mTOR results in the dephosphorylation, and thus activation, of the autophagic protein kinase ULK1, which is essential for autophagy activation during SAHA treatment. Furthermore, we show that the inhibition of autophagy by RNAi in glioblastoma cells results in an increase in SAHA-induced apoptosis. Importantly, when apoptosis is pharmacologically blocked, SAHA-induced nonapoptotic cell death can also be potentiated by autophagy inhibition. Overall, our findings indicate that SAHA activates autophagy via inhibiting mTOR and up-regulating LC3 expression; autophagy functions as a prosurvival mechanism to mitigate SAHA-induced apoptotic and nonapoptotic cell death, suggesting that targeting autophagy might improve the therapeutic effects of SAHA. PMID:22493260

Gammoh, Noor; Lam, Du; Puente, Cindy; Ganley, Ian; Marks, Paul A.; Jiang, Xuejun

2012-01-01

247

NR4A nuclear receptors support memory enhancement by histone deacetylase inhibitors.  

PubMed

The formation of a long-lasting memory requires a transcription-dependent consolidation period that converts a short-term memory into a long-term memory. Nuclear receptors compose a class of transcription factors that regulate diverse biological processes, and several nuclear receptors have been implicated in memory formation. Here, we examined the potential contribution of nuclear receptors to memory consolidation by measuring the expression of all 49 murine nuclear receptors after learning. We identified 13 nuclear receptors with increased expression after learning, including all 3 members of the Nr4a subfamily. These CREB-regulated Nr4a genes encode ligand-independent "orphan" nuclear receptors. We found that blocking NR4A activity in memory-supporting brain regions impaired long-term memory but did not impact short-term memory in mice. Further, expression of Nr4a genes increased following the memory-enhancing effects of histone deacetylase (HDAC) inhibitors. Blocking NR4A signaling interfered with the ability of HDAC inhibitors to enhance memory. These results demonstrate that the Nr4a gene family contributes to memory formation and is a promising target for improving cognitive function. PMID:22996661

Hawk, Joshua D; Bookout, Angie L; Poplawski, Shane G; Bridi, Morgan; Rao, Allison J; Sulewski, Michael E; Kroener, Brian T; Manglesdorf, David J; Abel, Ted

2012-10-01

248

Cardiac HDAC6 catalytic activity is induced in response to chronic hypertension  

Microsoft Academic Search

Small molecule histone deacetylase (HDAC) inhibitors block adverse cardiac remodeling in animal models of heart failure. The efficacious compounds target class I, class IIb and, to a lesser extent, class IIa HDACs. It is hypothesized that a selective inhibitor of a specific HDAC class (or an isoform within that class) will provide a favorable therapeutic window for the treatment of

Douglas D. Lemon; Todd R. Horn; Maria A. Cavasin; Mark Y. Jeong; Kurt W. Haubold; Carlin S. Long; David C. Irwin; Sylvia A. McCune; Eunhee Chung; Leslie A. Leinwand; Timothy A. McKinsey

2011-01-01

249

Induction of HDAC2 expression upon loss of APC in colorectal tumorigenesis  

Microsoft Academic Search

Inappropriate transcriptional repression involving histone deacetylases (HDACs) is a prominent cause for the development of leukemia. We now identify faulty expression of a specific mediator of transcriptional repression in a solid tumor. Loss of the adenomatosis polyposis coli (APC) tumor suppressor induces HDAC2 expression depending on the Wnt pathway and c-Myc. Increased HDAC2 expression is found in the majority of

Ping Zhu; Elke Martin; Jörg Mengwasser; Peter Schlag; Klaus-Peter Janssen; Martin Göttlicher

2004-01-01

250

Discovery of potent, isoform-selective inhibitors of histone deacetylase containing chiral heterocyclic capping groups and a N-(2-aminophenyl)benzamide binding unit.  

PubMed

The synthesis of a novel series of potent chiral inhibitors of histone deacetylase (HDAC) is described that contain a heterocyclic capping group and a N-(2-aminophenyl)benzamide unit that binds in the active site. In vitro assays for the inhibition of HDAC1, HDAC2, HDAC3-NCoR1, and HDAC8 by the N-(2-aminophenyl)benzamide 24a gave respective IC50 values of 930, 85, 12, and 4100 nM, exhibiting class I selectivity and potent inhibition of HDAC3-NCoR1. Both imidazolinone and thiazoline rings are shown to be effective replacements for the pyrimidine ring present in many other 2-(aminophenyl)benzamides previously reported, an example of each ring system at 1 ?M causing an increase in histone H3K9 acetylation in the human cell lines Jurkat and HeLa and an increase in cell death consistent with induction of apoptosis. Inhibition of the growth of MCF-7, A549, DU145, and HCT116 cell lines by 24a was observed, with respective IC50 values of 5.4, 5.8, 6.4, and 2.2 mM. PMID:23829483

Marson, Charles M; Matthews, Christopher J; Yiannaki, Elena; Atkinson, Stephen J; Soden, Peter E; Shukla, Lena; Lamadema, Nermina; Thomas, N Shaun B

2013-08-01

251

Histone deacetylase inhibitors modulate the transcriptional regulation of guanylyl cyclase/natriuretic peptide receptor-a gene: interactive roles of modified histones, histone acetyltransferase, p300, AND Sp1.  

PubMed

Atrial natriuretic peptide (ANP) binds guanylyl cyclase-A/natriuretic peptide receptor-A (GC-A/NPRA) and produces the intracellular second messenger, cGMP, which regulates cardiovascular homeostasis. We sought to determine the function of histone deacetylases (HDACs) in regulating Npr1 (coding for GC-A/NPRA) gene transcription, using primary mouse mesangial cells treated with class-specific HDAC inhibitors (HDACi). Trichostatin A, a pan inhibitor, and mocetinostat (MGCD0103), a class I HDAC inhibitor, significantly enhanced Npr1 promoter activity (by 8- and 10-fold, respectively), mRNA levels (4- and 5.3-fold, respectively), and NPRA protein (2.7- and 3.5-fold, respectively). However, MC1568 (class II HDAC inhibitor) had no discernible effect. Overexpression of HDAC1 and HDAC2 significantly attenuated Npr1 promoter activity, whereas HDAC3 and HDAC8 had no effect. HDACi-treated cultured cells in vitro and intact animals in vivo showed significantly reduced binding of HDAC1 and -2 and increased accumulation of acetylated H3-K9/14 and H4-K12 at the Npr1 promoter. Deletional analyses of the Npr1 promoter along with ectopic overexpression and inhibition of Sp1 confirmed that HDACi-induced Npr1 gene transcription is accomplished by Sp1 activation. Furthermore, HDACi attenuated the interaction of Sp1 with HDAC1/2 and promoted Sp1 association with p300 and p300/cAMP-binding protein-associated factor; it also promoted the recruitment of p300 and p300/cAMP-binding protein-associated factor to the Npr1 promoter. Our results demonstrate that trichostatin A and MGCD0103 enhanced Npr1 gene expression through inhibition of HDAC1/2 and increased both acetylation of histones (H3-K9/14, H4-K12) and Sp1 by p300, and their recruitment to Npr1 promoter. Our findings define a novel epigenetic regulatory mechanism that governs Npr1 gene transcription. PMID:24451378

Kumar, Prerna; Tripathi, Satyabha; Pandey, Kailash N

2014-03-01

252

Belinostat: a new broad acting antineoplastic histone deacetylase inhibitor.  

PubMed

Belinostat is a potent hydroxamate-type histone deacetylase inhibitor with a broad antineoplastic activity in a spectrum of preclinical tumor models and with demonstrated clinical efficacy in the still very early clinical trial program. Belinostat has been relatively well tolerated following both i.v. (from 30-min daily infusion to 48-h continuous infusion) and oral administration, and, since no or only minor bone marrow toxicity has been encountered, it has combined well with other antineoplastic agents in full doses. The clinical trial program needs to be advanced further before the final position of belinostat in the therapeutic anticancer armamentarium can be determined. PMID:19335278

Gimsing, Peter

2009-04-01

253

Histone deacetylase 6 inhibition improves memory and reduces total tau levels in a mouse model of tau deposition  

PubMed Central

Introduction Tau pathology is associated with a number of age-related neurodegenerative disorders. Few treatments have been demonstrated to diminish the impact of tau pathology in mouse models and none are yet effective in humans. Histone deacetylase 6 (HDAC6) is an enzyme that removes acetyl groups from cytoplasmic proteins, rather than nuclear histones. Its substrates include tubulin, heat shock protein 90 and cortactin. Tubastatin A is a selective inhibitor of HDAC6. Modification of tau pathology by specific inhibition of HDAC6 presents a potential therapeutic approach in tauopathy. Methods We treated rTg4510 mouse models of tau deposition and non-transgenic mice with tubastatin (25 mg/kg) or saline (0.9%) from 5 to 7 months of age. Cognitive behavior analysis, histology and biochemical analysis were applied to access the effect of tubastatin on memory, tau pathology and neurodegeneration (hippocampal volume). Results We present data showing that tubastatin restored memory function in rTg4510 mice and reversed a hyperactivity phenotype. We further found that tubastatin reduced the levels of total tau, both histologically and by western analysis. Reduction in total tau levels was positively correlated with memory improvement in these mice. However, there was no impact on phosphorylated forms of tau, either by histology or western analysis, nor was there an impact on silver positive inclusions histologically. Conclusion Potential mechanisms by which HDAC6 inhibitors might benefit the rTg4510 mouse include stabilization of microtubules secondary to increased tubulin acetylation, increased degradation of tau secondary to increased acetylation of HSP90 or both. These data support the use of HDAC6 inhibitors as potential therapeutic agents against tau pathology. PMID:24576665

2014-01-01

254

Histone-deacetylase Inhibition Reverses Atrial Arrhythmia Inducibility and Fibrosis in Cardiac Hypertrophy Independent of Angiotensin  

PubMed Central

Atrial fibrosis influences the development of atrial fibrillation (AF), particularly in the setting of structural heart disease where angiotensin-inhibition is partially effective for reducing atrial fibrosis and AF. Histone-deacetylase inhibition reduces cardiac hypertrophy and fibrosis, so we sought to determine if the HDAC inhibitor trichostatin A (TSA) could reduce atrial fibrosis and arrhythmias. Mice over-expressing homeodomain-only protein (HopXTg), which recruits HDAC activity to induce cardiac hypertrophy were investigated in 4 groups (aged 14-18 weeks): wild-type (WT), HopXTg, HopXTg mice treated with TSA for 2 weeks (HopX-TSA) and wild-type mice treated with TSA for 2 weeks (WT-TSA). These groups were characterized using invasive electrophysiology, atrial fibrosis measurements, atrial connexin immunocytochemistry and myocardial angiotensin II measurements. Invasive electrophysiologic stimulation, using the same attempts in each group, induced more atrial arrhythmias in HopXTg mice (48 episodes in 13 of 15 HopXTg mice versus 5 episodes in 2 of 15 HopX-TSA mice, P<0.001; versus 9 episodes in 2 of 15 WT mice, P<0.001; versus no episodes in any WT-TSA mice, P<0.001). TSA reduced atrial arrhythmia duration in HopXTg mice (1307±289 milliseconds versus 148±110 milliseconds, P<0.01) and atrial fibrosis (8.1±1.5% versus 3.9±0.4%, P<0.001). Atrial connexin40 was lower in HopXTg compared to WT mice, and TSA normalized the expression and size distribution of connexin40 gap junctions. Myocardial angiotensin II levels were similar between WT and HopXTg mice (76.3±26.0 versus 69.7±16.6 pg/mg protein, P=NS). Therefore, it appears HDAC inhibition reverses atrial fibrosis, connexin40 remodeling and atrial arrhythmia vulnerability independent of angiotensin II in cardiac hypertrophy. PMID:18926829

Liu, Fang; Levin, Mark D.; Petrenko, Nataliya B.; Lu, Min Min; Wang, Tao; Yuan, Li Jun; Stout, Andrea L.; Epstein, Jonathan A.; Patel, Vickas V.

2008-01-01

255

Epigenetic and molecular mechanisms underlying the antileukemic activity of the histone deacetylase inhibitor belinostat in human acute promyelocytic leukemia cells.  

PubMed

Therapeutic strategies targeting histone deacetylase (HDAC) inhibition have become promising in many human malignancies. Belinostat (PXD101) is a hydroxamate-type HDAC inhibitor tested in phase I and II clinical trials in solid tumors and hematological cancers. However, little is known about the use of belinostat for differentiation therapy against acute myelogenous leukemia. Here, we characterize the antileukemia activity of belinostat as a single drug and in combination with all-trans-retinoic acid (RA) in promyelocytic leukemia HL-60 and NB4 cells. Belinostat exerted dose-dependent growth-inhibitory or proapoptotic effects, promoting cell cycle arrest at the G0/G1 or the S transition. Apoptosis was accompanied by activation of caspase 3, degradation of PARP-1, and cell cycle-dependent changes in the expression of survivin, cyclin E1, and cyclin A2. Belinostat induced a dose-dependent reduction in the expression of EZH2 and SUZ12, HDAC-1, HDAC-2, and histone acetyltransferase PCAF (p300/CBP-associated factor). Belinostat increased acetylation of histone H4, H3 at K9 and H3 at K16 residues in a dose-dependent manner, but did not reduce trimethylation of H3 at K27 at proapoptotic doses. Combined treatment with belinostat and RA dose dependently accelerated and reinforced granulocytic differentiation, accompanied by changes in the expression of CD11b, C/EBP? (CCAAT/enhancer binding protein-?), and C/EBP?. Our results concluded the usefulness of belinostat, as an epigenetic drug, for antileukemia and differentiation therapy. PMID:24800886

Savickiene, Jurate; Treigyte, Grazina; Valiuliene, Giedre; Stirblyte, Ieva; Navakauskiene, Ruta

2014-09-01

256

Comparative genomics of the class 4 histone deacetylase family indicates a complex evolutionary history  

PubMed Central

Background Histone deacetylases are enzymes that modify core histones and play key roles in transcriptional regulation, chromatin assembly, DNA repair, and recombination in eukaryotes. Three types of related histone deacetylases (classes 1, 2, and 4) are widely found in eukaryotes, and structurally related proteins have also been found in some prokaryotes. Here we focus on the evolutionary history of the class 4 histone deacetylase family. Results Through sequence similarity searches against sequenced genomes and expressed sequence tag data, we identified members of the class 4 histone deacetylase family in 45 eukaryotic and 37 eubacterial species representative of very distant evolutionary lineages. Multiple phylogenetic analyses indicate that the phylogeny of these proteins is, in many respects, at odds with the phylogeny of the species in which they are found. In addition, the eukaryotic members of the class 4 histone deacetylase family clearly display an anomalous phyletic distribution. Conclusion The unexpected phylogenetic relationships within the class 4 histone deacetylase family and the anomalous phyletic distribution of these proteins within eukaryotes might be explained by two mechanisms: ancient gene duplication followed by differential gene losses and/or horizontal gene transfer. We discuss both possibilities in this report, and suggest that the evolutionary history of the class 4 histone deacetylase family may have been shaped by horizontal gene transfers. PMID:16884538

Ledent, Valérie; Vervoort, Michel

2006-01-01

257

The histone deacetylase inhibitor Trichostatin A modulates CD4+ T cell responses  

PubMed Central

Background Histone deacetylase inhibitors (HDACIs) induce hyperacetylation of core histones modulating chromatin structure and affecting gene expression. These compounds are also able to induce growth arrest, cell differentiation, and apoptotic cell death of tumor cells in vitro as well as in vivo. Even though several genes modulated by HDAC inhibition have been identified, those genes clearly responsible for the biological effects of these drugs have remained elusive. We investigated the pharmacological effect of the HDACI and potential anti-cancer agent Trichostatin A (TSA) on primary T cells. Methods To ascertain the effect of TSA on resting and activated T cells we used a model system where an enriched cell population consisting of primary T-cells was stimulated in vitro with immobilized anti-CD3/anti-CD28 antibodies whilst exposed to pharmacological concentrations of Trichostatin A. Results We found that this drug causes a rapid decline in cytokine expression, accumulation of cells in the G1 phase of the cell cycle, and induces apoptotic cell death. The mitochondrial respiratory chain (MRC) plays a critical role in the apoptotic response to TSA, as dissipation of mitochondrial membrane potential and reactive oxygen species (ROS) scavengers block TSA-induced T-cell death. Treatment of T cells with TSA results in the altered expression of a subset of genes involved in T cell responses, as assessed by microarray gene expression profiling. We also observed up- as well as down-regulation of various costimulatory/adhesion molecules, such as CD28 and CD154, important for T-cell function. Conclusions Taken together, our findings indicate that HDAC inhibitors have an immunomodulatory potential that may contribute to the potency and specificity of these antineoplastic compounds and might be useful in the treatment of autoimmune disorders. PMID:14606959

Moreira, José Manuel Afonso; Scheipers, Peter; Sørensen, Poul

2003-01-01

258

A structural insight into hydroxamic acid based histone deacetylase inhibitors for the presence of anticancer activity.  

PubMed

Histone deacetylase inhibitors (HDACi) have been actively explored as anti-cancer agents due to their ability to prevent deacetylation of histones, resulting in uncoiling of chromatin and stimulation of a range of genes associated in the regulation of cell survival, proliferation, differentiation and apoptosis. During the past several years, many HDACi have entered pre-clinical or clinical research as anti-cancer agents with satisfying results. Out of these, more than 8 novel hydroxamic acid based HDACi i.e., belinostat, abexinostat, SB939, resminostat, givinostat, quisinostat, pentobinostat, CUDC-101 are in clinical trials and one of the drug vorinostat (SAHA) has been approved by US FDA for cutaneous T-cell lymphoma (CTCL). It is clear from the plethora of new molecules and the encouraging results from clinical trials that this class of HDAC inhibitors hold a great deal of promise for the treatment of a variety of cancers. In this review, we classified the hydroxamic acid based HDACi on the basis of their structural features into saturated, unsaturated, branched, un-branched and 5, 6-membered cyclic ring linker present between zinc binding group and connecting unit. The present article enlists reports on hydroxamic acid based HDACi designed and developed using concepts of medicinal chemistry, demonstrating that hydroxamate derivatives represent a versatile class of compounds leading to novel imaging and therapeutic agents. This article will also provide a complete insight into various structural modifications required for optimum anticancer activity. PMID:23895688

Rajak, H; Singh, A; Raghuwanshi, K; Kumar, R; Dewangan, P K; Veerasamy, R; Sharma, P C; Dixit, A; Mishra, P

2014-01-01

259

The epigenetic modifier trichostatin A, a histone deacetylase inhibitor, suppresses proliferation and epithelial–mesenchymal transition of lens epithelial cells  

PubMed Central

Proliferation and epithelial–mesenchymal transition (EMT) of lens epithelium cells (LECs) may contribute to anterior subcapsular cataract (ASC) and posterior capsule opacification (PCO), which are important causes of visual impairment. Histone deacetylases (HDACs)-mediated epigenetic mechanism has a central role in controlling cell cycle regulation, cell proliferation and differentiation in a variety of cells and the pathogenesis of some diseases. However, whether HDACs are involved in the regulation of proliferation and EMT in LECs remain unknown. In this study, we evaluated the expression profile of HDAC family (18 genes) and found that class I and II HDACs were upregulated in transforming growth factor ?2 (TGF?2)-induced EMT in human LEC lines SRA01/04 and HLEB3. Tricostatin A (TSA), a class I and II HDAC inhibitor, suppressed the proliferation of LECs by G1 phase cell cycle arrest not only through inhibition of cyclin/CDK complexes and induction of p21 and p27, but also inactivation of the phosphatidylinositol-3-kinase/Akt, p38MAPK and ERK1/2 pathways. Meanwhile, TSA strongly prevented TGF?2-induced upregulation of fibronectin, collagen type I, collagen type IV, N-cadherin, Snail and Slug. We also demonstrated that the underlying mechanism of TSA affects EMT in LECs through inhibiting the canonical TGF?/Smad2 and the Jagged/Notch signaling pathways. Finally, we found that TSA completely prevented TGF?2-induced ASC in the whole lens culture semi-in vivo model. Therefore, this study may provide a new insight into the pathogenesis of ASC and PCO, and suggests that epigenetic treatment with HDAC inhibitors may be a novel therapeutic approach for the prevention and treatment of ASC, PCO and other fibrotic diseases. PMID:24157878

Chen, X; Xiao, W; Chen, W; Luo, L; Ye, S; Liu, Y

2013-01-01

260

Upregulation of KLF4 by methylseleninic acid in human esophageal squamous cell carcinoma cells: Modification of histone H3 acetylation through HAT/HDAC interplay.  

PubMed

Esophageal squamous cell carcinoma (ESCC) occurs at a very high frequency in certain areas of China. Supplementation with selenium-containing compounds was associated with a significantly lower cancer mortality rate in a study conducted in Linxia, China. Thus, selenium could be a potential anti-esophageal cancer agent. In this study, methylseleninic acid (MSA) could inhibit cell growth of ESCC cells in vitro and in vivo. Upon treated with MSA, the activity of histone deacetylases (HDACs) was decreased and general control nonrepressed protein 5 (GCN5) was upregulated in ESCC cells. Meanwhile, a significant increase of H3K9 acetylation (H3K9ac) was detected. Upregulation of Krüppel-like factor 4 (KLF4) was also observed after MSA treatment. Additionally, the acetylated histone H3 located more at KLF4 promoter region after MSA treatment, shown by chromatin immunoprecipitation (ChIP) assay. Moreover, knockdown of GCN5 decreased the protein level of both H3K9ac and KLF4, along with less cell growth inhibition. Taken all, our results indicated that MSA could inhibit ESCC cell growth, at least in part, by MSA-HDAC/GCN5-H3K9ac-KLF4 axis. To our best knowledge, this is the first report that MSA induced acetylation of histone H3 at Lys9, which might depend on the activities and the balance between HDACs and HATs. © 2014 Wiley Periodicals, Inc. PMID:24789055

Hu, Chenfei; Liu, Mei; Zhang, Wei; Xu, Qing; Ma, Kai; Chen, Lechuang; Wang, Zaozao; He, Shun; Zhu, Hongxia; Xu, Ningzhi

2014-05-01

261

Targeting of histone deacetylases to reactivate tumour suppressor genes and its therapeutic potential in a human cervical cancer xenograft model.  

PubMed

Aberrant histone acetylation plays an essential role in the neoplastic process via the epigenetic silencing of tumour suppressor genes (TSGs); therefore, the inhibition of histone deacetylases (HDAC) has become a promising target in cancer therapeutics. To investigate the correlation of histone acetylation with clinicopathological features and TSG expression, we examined the expression of acetylated H3 (AcH3), RAR?2, E-cadherin, and ?-catenin by immunohistochemistry in 65 cervical squamous cell carcinoma patients. The results revealed that the absence of AcH3 was directly associated with poor histological differentiation and nodal metastasis as well as reduced/negative expression of RAR?2, E-cadherin, and ?-catenin in clinical tumour samples. We further demonstrated that the clinically available HDAC inhibitors valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA), in combination with all-trans retinoic acid (ATRA), can overcome the epigenetic barriers to transcription of RAR?2 in human cervical cancer cells. Chromatin immunoprecipitation analysis showed that the combination treatment increased the enrichment of acetylated histone in the RAR?2-RARE promoter region. In view of these findings, we evaluated the antitumor effects induced by combined VPA and ATRA treatment in a xenograft model implanted with poorly differentiated human squamous cell carcinoma. Notably, VPA restored RAR?2 expression via epigenetic modulation. Additive antitumour effects were produced in tumour xenografts by combining VPA with ATRA treatment. Mechanistically, the combination treatment reactivated the expression of TSGs RAR?2, E-cadherin, P21 (CIP1) , and P53 and reduced the level of p-Stat3. Sequentially, upregulation of involucrin and loricrin, which indicate terminal differentiation, strongly contributed to tumour growth inhibition along with partial apoptosis. In conclusion, targeted therapy with HDAC inhibitors and RAR?2 agonists may represent a novel therapeutic approach for patients with cervical squamous cell carcinoma. PMID:24260446

Feng, Dingqing; Wu, Jiao; Tian, Yuan; Zhou, Hu; Zhou, Ying; Hu, Weiping; Zhao, Weidong; Wei, Haiming; Ling, Bin; Ma, Chunhong

2013-01-01

262

In vivo effects of Trichostatin A - A histone deacetylase inhibitor - On chromatin remodeling during Triturus cristatus spermatogenesis.  

PubMed

A major challenge in developmental biology field is to decipher the molecular mechanisms involved in cellular differentiation and to understand the processes that control and regulate genes expression. The study of nuclear molecular architecture during gametogenesis represents one approach toward deciphering the molecular organization and function of the eukaryotic chromatin. As spermatogenesis progresses, there is a widespread reorganization of the haploid genome followed by extensive DNA compaction. It is becoming increasingly evident that the dynamic composition of chromatin plays an important role in the activities of enzymes and in the processes that act upon it. As the information in the existing literature regarding the epigenetic modifications occurring in the advanced stages of spermatogenesis of crested newt is still scarce, we have investigated the effect of a Histone Deacetylase (HDAC) inhibitor, Trichostatin A (TSA), at the cytological level (by transmission electron microscopy - TEM, immunohistochemistry technique, fluorescence microscopy) and at the molecular level (AUT-PAGE and ChIP assay) on Triturus cristatus spermatogenesis. Our results have revealed an important role for regulation of histone deacetylase activity in controlling histone hyperacetylation and the replacement with sperm nuclear basic proteins during spermiogenesis. PMID:24100069

Burliba?a, Liliana; Zarnescu, Otilia

2013-11-01

263

Current evidence for histone deacetylase inhibitors in pancreatic cancer  

PubMed Central

Pancreatic cancer is one of the most aggressive human cancers, with more than 200?000 deaths worldwide every year. Despite recent efforts, conventional treatment approaches, such as surgery and classic chemotherapy, have only slightly improved patient outcomes. More effective and well-tolerated therapies are required to reverse the current poor prognosis of this type of neoplasm. Among new agents, histone deacetylase inhibitors (HDACIs) are now being tested. HDACIs have multiple biological effects related to acetylation of histones and many non-histone proteins that are involved in regulation of gene expression, apoptosis, cell cycle progression and angiogenesis. HDACIs induce cell cycle arrest and can activate the extrinsic and intrinsic pathways of apoptosis in different cancer cell lines. In the present review, the main mechanisms by which HDACIs act in pancreatic cancer cells in vitro, as well as their antiproliferative effects in animal models are presented. HDACIs constitute a promising treatment for pancreatic cancer with encouraging anti-tumor effects, at well-tolerated doses. PMID:23430136

Koutsounas, Ioannis; Giaginis, Constantinos; Patsouris, Efstratios; Theocharis, Stamatios

2013-01-01

264

Functional characteristics and gene expression profiles of primary acute myeloid leukaemia cells identify patient subgroups that differ in susceptibility to histone deacetylase inhibitors.  

PubMed

Modulation of gene expression through histone deacetylase (HDAC) inhibition is considered a possible therapeutic strategy in acute myeloid leukaemia (AML). In vitro effects and basal gene expression of structurally different HDAC inhibitors were examined. Primary human AML cells were derived from 59 consecutive patients. The HDAC inhibitors valproic acid, PXD101, trichostatin A and sodium butyrate inhibited leukaemic and clonogenic cell proliferation and increased apoptosis in a dose-dependent manner when tested at high concentrations. However, at lower concentrations proliferation increased for a subset of patients. This divergence was also observed in the presence of all-trans retinoic acid, theophylline and decitabine, and in cocultures with bone marrow stromal cells. Levels of IL-1beta, IL-6, GM-CSF and TNFalpha increased. Based on the basal expression of 100 genes the patients with growth enhancement at intermediate HDAC inhibitor concentrations and those without this response were clustered into two mutually exclusive groups. Functional characterization and gene expression analyses identify AML patient subsets that differ in their response to HDAC inhibitors. These observations may explain why HDAC inhibitor therapy affects only a subset of patients. PMID:17982680

Stapnes, Camilla; Ryningen, Anita; Hatfield, Kimberley; Øyan, Anne Margrete; Eide, Geir Egil; Corbascio, Matthias; Kalland, Karl-Henning; Gjertsen, Bjørn Tore; Bruserud, Øystein

2007-12-01

265

Histone Deacetylase Activity Represses Gamma Interferon-Inducible HLA-DR Gene Expression following the Establishment of a DNase I-Hypersensitive Chromatin Conformation  

PubMed Central

Expression of the retinoblastoma tumor suppressor protein (Rb) is required for gamma interferon (IFN-?)-inducible major histocompatibility complex class II gene expression and transcriptionally productive HLA-DRA promoter occupancy in several human tumor cell lines. Treatment of these Rb-defective tumor cell lines with histone deacetylase (HDAC) inhibitors rescued IFN-?-inducible HLA-DRA and -DRB mRNA and cell surface protein expression, demonstrating repression of these genes by endogenous cellular HDAC activity. Additionally, Rb-defective, transcriptionally incompetent tumor cells retained the HLA-DRA promoter DNase I-hypersensitive site. Thus, HDAC-mediated repression of the HLA-DRA promoter occurs following the establishment of an apparent nucleosome-free promoter region and before transcriptionally productive occupancy of the promoter by the required transactivators. Repression of HLA-DRA promoter activation by HDAC activity likely involves a YY1 binding element located in the first exon of the HLA-DRA gene. Chromatin immunoprecipitation experiments localized YY1 to the HLA-DRA gene in Rb-defective tumor cells. Additionally, mutation of the YY1 binding site prevented repression of the promoter by HDAC1 and partially prevented activation of the promoter by trichostatin A. Mutation of the octamer element also significantly reduced the ability of HDAC1 to confer repression of inducible HLA-DRA promoter activation. Treatment of Rb-defective tumor cells with HDAC inhibitors greatly reduced the DNA binding activity of Oct-1, a repressor of inducible HLA-DRA promoter activation. These findings represent the first evidence that HDAC activity can repress IFN-?-inducible HLA class II gene expression and also demonstrate that HDAC activity can contribute to promoter repression following the establishment of a DNase I-hypersensitive chromatin conformation. PMID:11533238

Osborne, Aaron; Zhang, Hongquan; Yang, Wen-Ming; Seto, Edward; Blanck, George

2001-01-01

266

Synthesis and biological characterization of spiro[2H-(1,3)-benzoxazine-2,4'-piperidine] based histone deacetylase inhibitors.  

PubMed

Histone Deacetylases (HDACs) have become important targets for the treatment of cancer and other diseases. In previous studies we described the development of novel spirocyclic HDAC inhibitors based on the combination of privileged structures with hydroxamic acid moieties as zinc binding group. Herein, we report further explorations, which resulted in the discovery of a new class of spiro[2H-(1,3)-benzoxazine-2,4'-piperidine] derivatives. Several compounds showed good potency of around 100 nM and less in the HDAC inhibition assays, submicromolar IC50 values when tested against tumour cell lines and a remarkable stability in human and mouse microsomes. Two representative examples exhibited a good pharmacokinetic profile with an oral bioavailability equal or higher than 35% and one of them studied in an HCT116 murine xenograft model showing a robust tumour growth inhibition. In addition, the two benzoxazines were found to have a minor affinity for the hERG potassium channel compared to their corresponding ketone analogues. PMID:23644210

Thaler, Florian; Varasi, Mario; Abate, Agnese; Carenzi, Giacomo; Colombo, Andrea; Bigogno, Chiara; Boggio, Roberto; Zuffo, Roberto Dal; Rapetti, Daniela; Resconi, Anna; Regalia, Nickolas; Vultaggio, Stefania; Dondio, Giulio; Gagliardi, Stefania; Minucci, Saverio; Mercurio, Ciro

2013-06-01

267

A single allele of Hdac2 but not Hdac1 is sufficient for normal mouse brain development in the absence of its paralog.  

PubMed

The histone deacetylases HDAC1 and HDAC2 are crucial regulators of chromatin structure and gene expression, thereby controlling important developmental processes. In the mouse brain, HDAC1 and HDAC2 exhibit different developmental stage- and lineage-specific expression patterns. To examine the individual contribution of these deacetylases during brain development, we deleted different combinations of Hdac1 and Hdac2 alleles in neural cells. Ablation of Hdac1 or Hdac2 by Nestin-Cre had no obvious consequences on brain development and architecture owing to compensation by the paralog. By contrast, combined deletion of Hdac1 and Hdac2 resulted in impaired chromatin structure, DNA damage, apoptosis and embryonic lethality. To dissect the individual roles of HDAC1 and HDAC2, we expressed single alleles of either Hdac1 or Hdac2 in the absence of the respective paralog in neural cells. The DNA-damage phenotype observed in double knockout brains was prevented by expression of a single allele of either Hdac1 or Hdac2. Strikingly, Hdac1(-/-)Hdac2(+/-) brains showed normal development and no obvious phenotype, whereas Hdac1(+/-)Hdac2(-/-) mice displayed impaired brain development and perinatal lethality. Hdac1(+/-)Hdac2(-/-) neural precursor cells showed reduced proliferation and premature differentiation mediated by overexpression of protein kinase C, delta, which is a direct target of HDAC2. Importantly, chemical inhibition or knockdown of protein kinase C delta was sufficient to rescue the phenotype of neural progenitor cells in vitro. Our data indicate that HDAC1 and HDAC2 have a common function in maintaining proper chromatin structures and show that HDAC2 has a unique role by controlling the fate of neural progenitors during normal brain development. PMID:24449838

Hagelkruys, Astrid; Lagger, Sabine; Krahmer, Julia; Leopoldi, Alexandra; Artaker, Matthias; Pusch, Oliver; Zezula, Jürgen; Weissmann, Simon; Xie, Yunli; Schöfer, Christian; Schlederer, Michaela; Brosch, Gerald; Matthias, Patrick; Selfridge, Jim; Lassmann, Hans; Knoblich, Jürgen A; Seiser, Christian

2014-02-01

268

The effects of the histone deacetylase inhibitor 4-phenylbutyrate on gap junction conductance and permeability  

PubMed Central

Longitudinal resistance is a key factor in determining cardiac action potential propagation. Action potential conduction velocity has been shown to be proportional to the square root of longitudinal resistance. A major determinant of longitudinal resistance in myocardium is the gap junction channel, comprised connexin proteins. Within the ventricular myocardium connexin43 (Cx43) is the dominantly expressed connexin. Reduced numbers of gap junction channels will result in an increase in longitudinal resistance creating the possibility of slowed conduction velocity while increased numbers of channels would potentially result in an increase in conduction velocity. We sought to determine if inhibition of histone deacetylase (HDAC) by 4-phenylbutyrate (4-PB), a known inhibitor of HDAC resulted in an increase in junctional conductance and permeability, which is not the result of changes in single channel unitary conductance. These experiments were performed using HEK-293 cells and HeLa cells stably transfected with Cx43. Following treatment with increasing concentrations of 4-PB up-regulation of Cx43 was observed via Western blot analysis. Junctional (gj) conductance and unitary single channel conductance were measured via whole-cell patch clamp. In addition intercellular transfer of lucifer yellow (LY) was determined by fluorescence microscopy. The data in this study indicate that 4-PB is able to enhance functional Cx43 gap junction coupling as indicated by LY dye transfer and multichannel and single channel data along with Western blot analysis. As a corollary, pharmacological agents such as 4-PB have the potential, by increasing intercellular coupling, to reduce the effect of ischemia. It remains to be seen whether drugs like 4-PB will be effective in preventing cardiac maladies. PMID:24027526

Kaufman, Joshua; Gordon, Chris; Bergamaschi, Roberto; Wang, Hong Z.; Cohen, Ira S.; Valiunas, Virginijus; Brink, Peter R.

2013-01-01

269

Histone deacetylase inhibitor, butyrate, attenuates lipopolysaccharide-induced acute lung injury in mice  

PubMed Central

Background Histone deacetylase (HDAC) inhibitors, developed as promising anti-tumor drugs, exhibit their anti-inflammatory properties due to their effects on reduction of inflammatory cytokines. Objective To investigate the protective effect of butyrate, a HDAC inhibitor, on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. Methods ALI was induced in Balb/c mice by intratracheally instillation of LPS (1 mg/kg). Before 1 hour of LPS administration, the mice received butyrate (10 mg/kg) orally. The animals in each group were sacrificed at different time point after LPS administration. Pulmonary histological changes were evaluated by hematoxylin-eosin stain and lung wet/dry weight ratios were observed. Concentrations of interleukin (IL)-1? and tumor necrosis factor (TNF)-? in bronchoalveolar lavage fluid (BALF) and concentrations of nitric oxide (NO) and myeloperoxidase (MPO) activity in lung tissue homogenates were measured by enzyme-linked immunosorbent assay (ELISA). Expression of nuclear factor (NF)-?B p65 in cytoplasm and nucleus was determined by Western blot analysis respectively. Results Pretreatment with butyrate led to significant attenuation of LPS induced evident lung histopathological changes, alveolar hemorrhage, and neutrophils infiltration with evidence of reduced MPO activity. The lung wet/dry weight ratios, as an index of lung edema, were reduced by butyrate administration. Butyrate also repressed the production of TNF-?, IL-1? and NO. Furthermore, the expression of NF-?B p65 in nucleus was markedly suppressed by butyrate pretreatment. Conclusions Butyrate had a protective effect on LPS-induced ALI, which may be related to its effect on suppression of inflammatory cytokines production and NF-?B activation. PMID:20302656

2010-01-01

270

A Systematic Assessment of Radiation Dose Enhancement by 5-Aza-2'-Deoxycytidine and Histone Deacetylase Inhibitors in Head-and-Neck Squamous Cell Carcinoma  

SciTech Connect

Purpose: Investigations of epigenetic drugs have shown that radiotherapy can be successfully combined with histone deacetylase inhibitors (HDAC-Is) for the treatment of head-and-neck squamous cell carcinoma (HNSCC). Whether the reversal of epigenetic silencing by demethylating agents with or without HDAC-Is can also act as radiosensitizing remains unclear. This study therefore aimed to investigate whether 5-aza-2'-deoxycytidine (DAC) alone or in combination with the HDAC-Is trichostatin A, LBH589, or MGCD0103 could radiosensitize HNSCC tumor cell lines. Methods and Materials: Histone acetylation status and expression of epigenetically silenced genes at the DNA, RNA, and protein levels were assessed as measures of drug effectiveness in six HNSCC cell lines. Based on their colony-forming capacity, colony assays were performed in four of six cell lines to evaluate the radiosensitizing potential of DAC with or without HDAC-Is. Additional assays of cell survival, apoptosis, cell proliferation, and DNA damage were performed. Results: Radiosensitization was observed in two HNSCC cell lines treated with noncytotoxic doses of DAC with or without HDAC-Is before irradiation. The radiosensitizing doses induced histone hyperacetylation and reversal of gene silencing to variable extents and increased radiation-induced cell-cycle arrest. Conclusions: A role for low-dose DAC with or without HDAC-Is as radiosensitizers in HNSCC seems promising and is supportive of future clinical use, especially for combinations of DAC with LBH589 or MGCD0103, although the mechanisms by which they work will require further study.

Schutter, Harlinde de; Kimpe, Marlies; Isebaert, Sofie [Laboratory of Experimental Radiotherapy, Leuvens Kanker Instituut, University Hospitals Leuven, Leuven (Belgium); Nuyts, Sandra [Laboratory of Experimental Radiotherapy, Leuvens Kanker Instituut, University Hospitals Leuven, Leuven (Belgium); Department of Radiation Oncology, Leuvens Kanker Instituut, University Hospitals Leuven, Leuven (Belgium)], E-mail: sandra.nuyts@uzleuven.be

2009-03-01

271

Histone H3 Lysine 36 Methylation Antagonizes Silencing in Saccharomyces cerevisiae Independently of the Rpd3S Histone Deacetylase Complex  

Microsoft Academic Search

In yeast, methylation of histone H3 on lysine 36 (H3-K36) is catalyzed by the NSD1 leukemia on- coprotein homolog Set2. The histone deacetylase complex Rpd3S is recruited to chromatin via binding of the chromodomain protein Eaf3 to methylated H3-K36 to prevent erroneous transcription initiation. Here we identify a distinct function for H3-K36 methylation. We used random mutagenesis of histones H3

Rachel Tompa; Hiten D. Madhani

2007-01-01

272

Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias  

PubMed Central

MS-275 is a benzamide derivative with potent histone deacetylase (HDAC) inhibitory and antitumor activity in preclinical models. We conducted a phase 1 trial of orally administered MS-275 in 38 adults with advanced acute leukemias. Cohorts of patients were treated with MS-275 initially once weekly × 2, repeated every 4 weeks from 4 to 8 mg/m2, and after 13 patients were treated, once weekly × 4, repeated every 6 weeks from 8 to 10 mg/m2. The maximum-tolerated dose was 8 mg/m2 weekly for 4 weeks every 6 weeks. Dose-limiting toxicities (DLTs) included infections and neurologic toxicity manifesting as unsteady gait and somnolence. Other frequent non-DLTs were fatigue, anorexia, nausea, vomiting, hypoalbuminemia, and hypocalcemia. Treatment with MS-275 induced increase in protein and histone H3/H4 acetylation, p21 expression, and caspase-3 activation in bone marrow mononuclear cells. No responses by classical criteria were seen. Our results show that MS-275 effectively inhibits HDAC in vivo in patients with advanced myeloid leukemias and should be further tested, preferably in patients with less-advanced disease. PMID:17179232

Jiemjit, Anchalee; Trepel, Jane B.; Sparreboom, Alex; Figg, William D.; Rollins, Sandra; Tidwell, Michael L.; Greer, Jacqueline; Chung, Eun Joo; Lee, Min-Jung; Gore, Steven D.; Sausville, Edward A.; Zwiebel, James; Karp, Judith E.

2007-01-01

273

Adenovirus assembly is impaired by BMI1-related histone deacetylase activity.  

PubMed

Polycomb ring finger oncogene BMI1 (B cell-specific Moloney murine leukemia virus integration site 1) plays a critical role in development of several types of cancers. Here, we report an inverse relationship between levels of BMI1 expression and adenovirus (Ad) progeny production. Enforced BMI1 expression in A549 cells impaired Ad progeny production. In contrast, knocking-down of endogenous BMI1 expression enhanced progeny production of a conditionally replicating Ad and wild-type Ad5 and Ad11p. Ad vectors overexpressing BMI1 were not impaired in the replication of progeny genomes and in the expression of E1A and Ad structural proteins. However, 293 cells infected by Ad vector overexpressing BMI1 contained a large proportion of morphologically irregular Ad particles. This effect was reversed in 293 cells pre-treated with the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) in parallel with the production of infectious Ad particles. Our findings suggest an inhibitory role of BMI1 in Ad morphogenesis that can be implied in Ad tropism and Ad-mediated cancer therapy. PMID:24889242

Na, Manli; Chen, Dongfeng; Holmqvist, Bo; Ran, Liang; Jin, Jie; Rebetz, Johan; Fan, Xiaolong

2014-05-01

274

Carfilzomib interacts synergistically with histone deacetylase inhibitors in mantle cell lymphoma cells in vitro and in vivo.  

PubMed

Interactions between the proteasome inhibitor carfilzomib and the histone deacetylase (HDAC) inhibitors vorinostat and SNDX-275 were examined in mantle cell lymphoma (MCL) cells in vitro and in vivo. Coadministration of very low, marginally toxic carfilzomib concentrations (e.g., 3-4 nmol/L) with minimally lethal vorinostat or SNDX-275 concentrations induced sharp increases in mitochondrial injury and apoptosis in multiple MCL cell lines and primary MCL cells. Enhanced lethality was associated with c-jun-NH,-kinase (JNK) 1/2 activation, increased DNA damage (induction of ?H2A.X), and ERK1/2 and AKT1/2 inactivation. Coadministration of carfilzomib and histone deacetylase inhibitors (HDACI) induced a marked increase in reactive oxygen species (ROS) generation and G(2)-M arrest. Significantly, the free radical scavenger tetrakis(4-benzoic acid) porphyrin (TBAP) blocked carfilzomib/HDACI-mediated ROS generation, ?H2A.X formation, JNK1/2 activation, and lethality. Genetic (short hairpin RNA) knockdown of JNK1/2 significantly attenuated carfilzomib/HDACI-induced apoptosis, but did not prevent ROS generation or DNA damage. Carfilzomib/HDACI regimens were also active against bortezomib-resistant MCL cells. Finally, carfilzomib/vorinostat coadministration resulted in a pronounced reduction in tumor growth compared with single agent treatment in an MCL xenograft model associated with enhanced apoptosis, ?H2A.X formation, and JNK activation. Collectively, these findings suggest that carfilzomib/HDACI regimens warrant attention in MCL. PMID:21750224

Dasmahapatra, Girija; Lembersky, Dmitry; Son, Minkyeong P; Attkisson, Elisa; Dent, Paul; Fisher, Richard I; Friedberg, Jonathan W; Grant, Steven

2011-09-01

275

The promise and perils of HDAC inhibitors in neurodegeneration  

PubMed Central

Histone deacetylases (HDACs) represent emerging therapeutic targets in the context of neurodegeneration. Indeed, pharmacologic inhibition of HDACs activity in the nervous system has shown beneficial effects in several preclinical models of neurological disorders. However, the translation of such therapeutic approach to clinics has been only marginally successful, mainly due to our still limited knowledge about HDACs physiological role particularly in neurons. Here, we review the potential benefits along with the risks of targeting HDACs in light of what we currently know about HDAC activity in the brain. PMID:25642438

Didonna, Alessandro; Opal, Puneet

2015-01-01

276

Inhibition and mechanism of HDAC8 revisited.  

PubMed

Histone deacetylases (HDACs) have found intense interest as drug targets for a variety of diseases, but there is disagreement about basic aspects of the inhibition and mechanism of HDACs. QM/MM calculations of HDAC8 including a large QM region provide a model that is consistent with the available crystal structures and structure-activity relationships of different HDAC inhibitors. The calculations support a spontaneous proton transfer from a hydroxamic acid to an active site histidine upon binding to the zinc. The role of the H142/D176 catalytic dyad as the general base of the reaction is elucidated. The reasons for the disagreements between previous proposals are discussed. The results provide detailed insights into the unique mechanism of HDACs, including the role of the two catalytic dyads and function of the potassium near the active site. They also have important implications for the design of novel inhibitors for a number of HDACs such as the class IIa HDACs. PMID:25060069

Chen, Kai; Zhang, Xiaoxiao; Wu, Yun-Dong; Wiest, Olaf

2014-08-20

277

Noninvasive Magnetic Resonance Spectroscopic Pharmacodynamic Markers of a Novel Histone Deacetylase Inhibitor, LAQ824, in Human Colon Carcinoma Cells and Xenografts1  

PubMed Central

The aim of this work was to use phosphorus magnetic resonance spectroscopy (31P MRS) to investigate the pharmacodynamic effects of LAQ824, a histone deacetylase (HDAC) inhibitor. Human HT29 colon carcinoma cells were examined by 31P MRS after treatment with LAQ824 and another HDAC inhibitor, suberoylanilide hydroxamic acid. HT29 xenografts and tumor extracts were also examined using 31P MRS, pre- and post-LAQ824 treatment. Histone H3 acetylation was determined using Western blot analysis, and tumor microvessel density by immunohistochemical staining of CD31. Phosphocholine showed a significant increase in HT29 cells after treatment with LAQ824 and suberoylanilide hydroxamic acid. In vivo, the ratio of phosphomonoester/total phosphorus (TotP) signal was significantly increased in LAQ824-treated HT29 xenografts, and this ratio was inversely correlated with changes in tumor volume. Statistically significant decreases in intracellular pH, ?-nucleoside triphosphate (?-NTP)/TotP, and ?-NTP/inorganic phosphate (Pi) and an increase in Pi/TotP were also seen in LAQ824-treated tumors. Tumor extracts showed many significant metabolic changes after LAQ824 treatment, in parallel with increased histone acetylation and decreased microvessel density. Treatment with LAQ824 resulted in altered phospholipid metabolism and compromised tumor bioenergetics. The phosphocholine and phosphomonoester increases may have the potential to act as pharmacodynamic markers for noninvasively monitoring tumor response after treatment with LAQ824 or other HDAC inhibitors. PMID:18392140

Chung, Yuen-Li; Troy, Helen; Kristeleit, Rebecca; Aherne, Wynne; Jackson, L Elizabeth; Atadja, Peter; Griffiths, John R; Judson, Ian R; Workman, Paul; Leach, Martin O; Beloueche-Babari, Mounia

2008-01-01

278

Pentyl-4-yn-VPA, a histone deacetylase inhibitor, ameliorates deficits in social behavior and cognition in a rodent model of autism spectrum disorders.  

PubMed

In utero exposure of rodents to valproic acid (VPA) has been proposed to induce an adult phenotype with behavioural characteristics reminiscent of those observed in autism spectrum disorder (ASD). Our previous studies have demonstrated the social cognition deficits observed in this model, a major core symptom of ASD, to be ameliorated following chronic administration of histone deacetylase (HDAC) inhibitors. Using this model, we now demonstrate pentyl-4-yn-VPA, an analogue of valproate and HDAC inhibitor, to significantly ameliorate deficits in social cognition as measured using the social approach avoidance paradigm as an indicator of social reciprocity and spatial learning to interrogate dorsal stream cognitive processing. The effects obtained with pentyl-4-yn-VPA were found to be similar to those obtained with SAHA, a pan-specific HDAC inhibitor. Histones isolated from the cerebellar cortex and immunoblotted with antibodies recognising lysine-specific modification revealed SAHA and pentyl-4-yn-VPA to enhance the acetylation status of H4K8. Additionally, the action of pentyl-4-yn-VPA, could be differentiated from that of SAHA by its ability to decrease H3K9 acetylation and enhance H3K14 acetylation. The histone modifications mediated by pentyl-4-yn-VPA are suggested to act cooperatively through differential acetylation of the promoter and transcription regions of active genes. PMID:24486700

Foley, Andrew G; Cassidy, Andrew W; Regan, Ciaran M

2014-03-15

279

Histone Deacetylase AtHDA7 Is Required for Female Gametophyte and Embryo Development in Arabidopsis1[C][W][OPEN  

PubMed Central

Histone modifications are involved in the regulation of many processes in eukaryotic development. In this work, we provide evidence that AtHDA7, a HISTONE DEACETYLASE (HDAC) of the Reduced Potassium Dependency3 (RPD3) superfamily, is crucial for female gametophyte development and embryogenesis in Arabidopsis (Arabidopsis thaliana). Silencing of AtHDA7 causes degeneration of micropylar nuclei at the stage of four-nucleate embryo sac and delay in the progression of embryo development, thereby bringing the seed set down in the Athda7-2 mutant. Furthermore, AtHDA7 down- and up-regulation lead to a delay of growth in postgermination and later developmental stages. The Athda7-2 mutation that induces histone hyperacetylation significantly increases the transcription of other HDACs (AtHDA6 and AtHDA9). Moreover, silencing of AtHDA7 affects the expression of ARABIDOPSIS HOMOLOG OF SEPARASE (AtAESP), previously demonstrated to be involved in female gametophyte and embryo development. However, chromatin immunoprecipitation analysis with acetylated H3 antibody provided evidence that the acetylation levels of H3 at AtAESP and HDACs does not change in the mutant. Further investigations are essential to ascertain the mechanism by which AtHDA7 affects female gametophyte and embryo development. PMID:23878078

Cigliano, Riccardo Aiese; Cremona, Gaetana; Paparo, Rosa; Termolino, Pasquale; Perrella, Giorgio; Gutzat, Ruben; Consiglio, Maria Federica; Conicella, Clara

2013-01-01

280

Specific inhibition of histone deacetylase 8 reduces gene expression and production of proinflammatory cytokines in vitro and in vivo.  

PubMed

ITF2357 (generic givinostat) is an orally active, hydroxamic-containing histone deacetylase (HDAC) inhibitor, with broad anti-inflammatory properties and which has been used to treat children with systemic juvenile idiopathic arthritis. ITF2357 inhibits both Class I and II HDACs, reduces caspase 1 activity in human peripheral blood mononuclear cells (PBMC) and the secretion of IL 1? and other cytokines at 25-100 nM; at concentrations >200nM, ITF2357 is toxic in vitro. ITF3056, an analogue of ITF2357, inhibits only HDAC8 (IC50 285 nM). Here we compared the production of IL 1?, IL 1?, TNF? and IL 6 by ITF2357 to that of ITF3056 in PBMC stimulated with lipopolysaccharide (LPS), heat-killed Candida albicans or anti-CD3/anti-CD28 antibodies. ITF3056 reduced LPS-induced cytokines from 100 to 1000 nM; at 1000 nM, the secretion of IL 1? was reduced by 76%, TNF? by 88% and IL 6 by 61%. The intracellular levels of IL 1? were 30% lower. There was no evidence of cell toxicity at concentrations of ITF3056 (100 to 1000nM). Gene expression of TNF? was markedly reduced (80%) whereas IL 6 gene expression was 40% lower. Although anti-CD3/28 and Candida stimulation of IL 1? and TNF? was modestly reduced, IFN? production was 75% lower. Mechanistically, ITF3056 reduced the secretion of processed IL 1? independent of inhibition of caspase 1 activity; however, synthesis of the IL 1? precursor was reduced by 40% without significant decrease in IL 1? mRNA levels. In mice, ITF3056 reduced LPS-induced serum TNF? by 85% and IL 1? by 88%. These data suggest that specific inhibition of HDAC8 results in reduced inflammation without cell toxicity. PMID:25451941

Li, Suzhao; Fossati, Gianluca; Marchetti, Carlo; Modena, Daniela; Pozzi, Pietro; Reznikov, Leonid L; Azam, Tania; Abbate, Antonio; Mascagni, Paolo; Dinarello, Charles A

2014-12-01

281

Association of estrogen receptor alpha and histone deacetylase 6 causes rapid deacetylation of tubulin in breast cancer cells.  

PubMed

Estrogen receptor alpha (ERalpha) is a nuclear receptor that functions as a ligand-activated transcription factor. Besides its genomic action in nuclei, ERalpha could exert nongenomic actions at the plasma membrane. To investigate the mechanism underlying the nongenomic action of ERalpha in breast cancer cells, we generated a construct of membrane-targeted ERalpha (memER), an expression vector of ERalpha without the nuclear localizing signal and including instead the membrane-targeting sequence of Src kinase. MemER was stably expressed in human breast cancer MCF-7 cells. Cell migration test and tumorigenic assay in nude mice revealed that the in vitro motility and the in vivo proliferation activity of MCF-7 cells expressing memER were significantly enhanced compared with those of vector-transfected cells. Interestingly, the acetylation level of tubulin in memER-overexpressing cells was lower than that in control cells. We found that histone deacetylase (HDAC) 6 translocated to the plasma membrane shortly after estrogen stimulation, and rapid tubulin deacetylation subsequently occurred. We also showed that memER associated with HDAC6 in a ligand-dependent manner. Although tamoxifen is known for its antagonistic role in the ERalpha genomic action in MCF-7 cells, the agent showed an agonistic function in the memER-HDAC6 association and tubulin deacetylation. These findings suggest that ERalpha ligand dependently forms a complex with HDAC6 and tubulin at the plasma membrane. Estrogen-dependent tubulin deacetylation could provide new evidence for the nongenomic action of estrogen, which potentially contributes to the aggressiveness of ERalpha-positive breast cancer cells. PMID:19318565

Azuma, Kotaro; Urano, Tomohiko; Horie-Inoue, Kuniko; Hayashi, Shin-ichi; Sakai, Ryuichi; Ouchi, Yasuyoshi; Inoue, Satoshi

2009-04-01

282

Arsenic toxicity induced endothelial dysfunction and dementia: Pharmacological interdiction by histone deacetylase and inducible nitric oxide synthase inhibitors  

SciTech Connect

Arsenic toxicity has been reported to damage all the major organs including the brain and vasculature. Dementia including Alzheimer's disease (AD) and vascular dementia (VaD) are posing greater risk to the world population as it is now increasing at a faster rate. We have investigated the role of sodium butyrate, a selective histone deacetylase (HDAC) inhibitor and aminoguanidine, a selective inducible nitric oxide synthase (iNOS) inhibitor in pharmacological interdiction of arsenic toxicity induced vascular endothelial dysfunction and dementia in rats. Arsenic toxicity was done by administering arsenic drinking water to rats. Morris water-maze (MWM) test was used for assessment of learning and memory. Endothelial function was assessed using student physiograph. Oxidative stress (aortic superoxide anion, serum and brain thiobarbituric acid reactive species, brain glutathione) and nitric oxide levels (serum nitrite/nitrate) were also measured. Arsenic treated rats have shown impairment of endothelial function, learning and memory, reduction in serum nitrite/nitrate and brain GSH levels along with increase in serum and brain TBARS. Sodium butyrate as well as aminoguanidine significantly convalesce arsenic induced impairment of learning, memory, endothelial function, and alterations in various biochemical parameters. It may be concluded that arsenic induces endothelial dysfunction and dementia, whereas, sodium butyrate, a HDAC inhibitor as well as aminoguanidine, a selective iNOS inhibitor may be considered as potential agents for the management of arsenic induced endothelial dysfunction and dementia. - Highlights: • As has induced endothelial dysfunction (Edf) and vascular dementia (VaD). • As has increased oxidative stress, AChE activity and decreased serum NO. • Inhibitors of HDAC and iNOS have attenuated As induced Edf and VaD. • Both the inhibitors have attenuated As induced biochemical changes. • Inhibitor of HDAC and iNOS has shown good potential in As induced VaD.

Sharma, Bhupesh, E-mail: drbhupeshresearch@gmail.com; Sharma, P.M.

2013-11-15

283

HDAC6 and Ovarian Cancer  

PubMed Central

The special class IIb histone deacetylase, HDAC6, plays a prominent role in many cellular processes related to cancer, including oncogenesis, the cell stress response, motility, and myriad signaling pathways. Many of the lessons learned from other cancers can be applied to ovarian cancer as well. HDAC6 interacts with diverse proteins such as HSP90, cortactin, tubulin, dynein, p300, Bax, and GRK2 in both the nucleus and cytoplasm to carry out these cancerous functions. Not all pro-cancer interactions of HDAC6 involve deacetylation. The idea of using HDAC6 as a target for cancer treatment continues to expand in recent years, and more potent and specific HDAC6 inhibitors are required to effectively down-regulate the tumor-prone cell signaling pathways responsible for ovarian cancer. PMID:23644884

Haakenson, Joshua; Zhang, Xiaohong

2013-01-01

284

Unspliced X-box-binding protein 1 (XBP1) protects endothelial cells from oxidative stress through interaction with histone deacetylase 3.  

PubMed

It is well known that atherosclerosis occurs geographically at branch points where disturbed flow predisposes to the development of plaque via triggering of oxidative stress and inflammatory reactions. In this study, we found that disturbed flow activated anti-oxidative reactions via up-regulating heme oxygenase 1 (HO-1) in an X-box-binding protein 1 (XBP1) and histone deacetylase 3 (HDAC3)-dependent manner. Disturbed flow concomitantly up-regulated the unspliced XBP1 (XBP1u) and HDAC3 in a VEGF receptor and PI3K/Akt-dependent manner. The presence of XBP1 was essential for the up-regulation of HDAC3 protein. Overexpression of XBP1u and/or HDAC3 activated Akt1 phosphorylation, Nrf2 protein stabilization and nuclear translocation, and HO-1 expression. Knockdown of XBP1u decreased the basal level and disturbed flow-induced Akt1 phosphorylation, Nrf2 stabilization, and HO-1 expression. Knockdown of HDAC3 ablated XBP1u-mediated effects. The mammalian target of rapamycin complex 2 (mTORC2) inhibitor, AZD2014, ablated XBP1u or HDAC3 or disturbed flow-mediated Akt1 phosphorylation, Nrf2 nuclear translocation, and HO-1 expression. Neither actinomycin D nor cycloheximide affected disturbed flow-induced up-regulation of Nrf2 protein. Knockdown of Nrf2 abolished XBP1u or HDAC3 or disturbed flow-induced HO-1 up-regulation. Co-immunoprecipitation assays demonstrated that XBP1u physically bound to HDAC3 and Akt1. The region of amino acids 201 to 323 of the HDAC3 protein was responsible for the binding to XBP1u. Double immunofluorescence staining revealed that the interactions between Akt1 and mTORC2, Akt1 and HDAC3, Akt1 and XBP1u, HDAC3, and XBP1u occurred in the cytosol. Thus, we demonstrate that XBP1u and HDAC3 exert a protective effect on disturbed flow-induced oxidative stress via up-regulation of mTORC2-dependent Akt1 phosphorylation and Nrf2-mediated HO-1 expression. PMID:25190803

Martin, Daniel; Li, Yi; Yang, Junyao; Wang, Gang; Margariti, Andriana; Jiang, Zhixin; Yu, Hui; Zampetaki, Anna; Hu, Yanhua; Xu, Qingbo; Zeng, Lingfang

2014-10-31

285

The effects of a histone deacetylase inhibitor on biological behavior of diffuse large B-cell lymphoma cell lines and insights into the underlying mechanisms  

PubMed Central

Background Epigenetic control using histone deacetylase (HDAC) inhibitors is a promising therapy for lymphomas. Insights into the anti-proliferative effects of HDAC inhibitors on diffuse large B-cell lymphoma (DLBCL) and further understanding of the underlying mechanisms, which remain unclear to date, are of great importance. Methods Three DLBCL cell lines (DoHH2, LY1 and LY8) were used to define the potential epigenetic targets for Trichostatin A (TSA)-mediated anti-proliferative effects via CCK-8 assay. Cell cycle distribution and apoptosis were detected by flow cytometry. We further investigated the underlying molecular mechanisms by examining expression levels of relevant proteins using western blot analysis. Results TSA treatment inhibited the growth of all three DLBCL cell lines and enhanced cell cycle arrest and apoptosis. Molecular analysis revealed upregulated acetylation of histone H3, ?-tubulin and p53, and dephosphorylation of pAkt with altered expression of its main downstream effectors (p21, p27, cyclin D1 and Bcl-2). HDAC profiling revealed that all three cell lines had varying HDAC1–6 expression levels, with the highest expression of all six isoforms, in DoHH2 cells, which displayed the highest sensitivity to TSA. Conclusion Our results demonstrated that the HDAC inhibitor TSA inhibited DLBCL cell growth, and that cell lines with higher expression of HDACs tended to be more sensitive to TSA. Our data also suggested that inhibition of pAkt and activation of p53 pathway are the main molecular events involved in inhibitory effects of TSA. PMID:23758695

2013-01-01

286

Profiling of substrates for zinc-dependent lysine deacylase enzymes: HDAC3 exhibits decrotonylase activity in vitro.  

PubMed

Systematic screening of the activities of the eleven human zinc-dependent lysine deacylases against a series of fluorogenic substrates as well as kinetic evaluation revealed substrates for screenings of histone deacetylases HDAC10 and HDAC11 at reasonably low enzyme concentrations. Furthermore, HDAC3 in complex with nuclear receptor corepressor 1 (HDAC3-NCoR1) was shown to harbor decrotonylase activity in vitro. PMID:22890609

Madsen, Andreas S; Olsen, Christian A

2012-09-01

287

PCI-24781 (abexinostat), a novel histone deacetylase inhibitor, induces reactive oxygen species-dependent apoptosis and is synergistic with bortezomib in neuroblastoma  

PubMed Central

In this study, we investigated the cytotoxic effects of a broad-spectrum histone deacetylase (HDAC) inhibitor, PCI-24781, alone and in combination with the proteasome inhibitor bortezomib in neuroblastoma cell lines. The combination was shown to induce synergistic cytotoxity involving the formation of reactive oxygen species. The cleavage of caspase-3 and PARP, as determined by western blotting, indicated that cell death was primarily due to apoptosis. Xenograft mouse models indicated increased survival among animals treated with this combination. The Notch signaling pathway and MYCN gene expression were quantified by reverse transcription-polymerase chain reaction (PCR) in cells treated with PCI-24781 and bortezomib, alone and in combination. Notch pathway expression increased in response to an HDAC inhibitor. NFKB1 and MYCN were both significantly down regulated. Our results suggest that PCI-24781 and bortezomib are synergistic in neuroblastoma cell lines and may be a new therapeutic strategy for this disease. PMID:25520806

Sholler, Giselle Saulnier; Currier, Erika A.; Dutta, Akshita; Slavik, Marni A.; Illenye, Sharon A.; Mendonca, Maria Cecilia F.; Dragon, Julie; Roberts, Stephen S.; Bond, Jeffrey P.

2014-01-01

288

The acetylome regulators Hdac1 and Hdac2 differently modulate intestinal epithelial cell dependent homeostatic responses in experimental colitis.  

PubMed

Histone deacetylases (Hdac) remove acetyl groups from proteins, influencing global and specific gene expression. Hdacs control inflammation, as shown by Hdac inhibitor-dependent protection from dextran sulfate sodium (DSS)-induced murine colitis. Although tissue-specific Hdac knockouts show redundant and specific functions, little is known of their intestinal epithelial cell (IEC) role. We have shown previously that dual Hdac1/Hdac2 IEC-specific loss disrupts cell proliferation and determination, with decreased secretory cell numbers and altered barrier function. We thus investigated how compound Hdac1/Hdac2 or Hdac2 IEC-specific deficiency alters the inflammatory response. Floxed Hdac1 and Hdac2 and villin-Cre mice were interbred. Compound Hdac1/Hdac2 IEC-deficient mice showed chronic basal inflammation, with increased basal disease activity index (DAI) and deregulated Reg gene colonic expression. DSS-treated dual Hdac1/Hdac2 IEC-deficient mice displayed increased DAI, histological score, intestinal permeability, and inflammatory gene expression. In contrast to double knockouts, Hdac2 IEC-specific loss did not affect IEC determination and growth, nor result in chronic inflammation. However, Hdac2 disruption protected against DSS colitis, as shown by decreased DAI, intestinal permeability and caspase-3 cleavage. Hdac2 IEC-specific deficient mice displayed increased expression of IEC gene subsets, such as colonic antimicrobial Reg3b and Reg3g mRNAs, and decreased expression of immune cell function-related genes. Our data show that Hdac1 and Hdac2 are essential IEC homeostasis regulators. IEC-specific Hdac1 and Hdac2 may act as epigenetic sensors and transmitters of environmental cues and regulate IEC-mediated mucosal homeostatic and inflammatory responses. Different levels of IEC Hdac activity may lead to positive or negative outcomes on intestinal homeostasis during inflammation. PMID:24525021

Turgeon, Naomie; Gagné, Julie Moore; Blais, Mylène; Gendron, Fernand-Pierre; Boudreau, François; Asselin, Claude

2014-04-01

289

The histone deacetylase inhibitor, LBH589, promotes the systemic cytokine and effector responses of adoptively transferred CD8+ T cells  

PubMed Central

Background Histone deacetylase (HDAC) inhibitors are a class of agents that have potent antitumor activity with a reported ability to upregulate MHC and costimulatory molecule expression. We hypothesized that epigenetic pharmacological immunomodulation could sensitize tumors to immune mediated cell death with an adoptive T cell therapy. Methods The pan-HDAC inhibitor, LBH589, was combined with gp100 specific T cell immunotherapy in an in vivo B16 melanoma model and in an in vivo non-tumor bearing model. Tumor regression, tumor specific T cell function and phenotype, and serum cytokine levels were evaluated. Results Addition of LBH589 to an adoptive cell transfer therapy significantly decreased tumor burden while sustaining systemic pro-inflammatory levels. Furthermore, LBH589 was able to enhance gp100 specific T cell survival and significantly decrease T regulatory cell populations systemically and intratumorally. Even in the absence of tumor, LBH589 was able to enhance the proliferation, retention, and polyfunctional status of tumor specific T cells, suggesting its effects were T cell specific. In addition, LBH589 induced significantly higher levels of the IL-2 receptor (CD25) and the co-stimulatory molecule OX-40 in T cells. Conclusion These results demonstrate that immunomodulation of adoptively transferred T cells by LBH589 provides a novel mechanism to increase in vivo antitumor efficacy of effector CD8 T cells. PMID:25054063

2014-01-01

290

A new histone deacetylase inhibitor improves liver fibrosis in BDL rats through suppression of hepatic stellate cells  

PubMed Central

Background and Purpose Activation of hepatic stellate cells (HSCs) is a crucial step in the pathogenesis of hepatic fibrosis. Histone deacetylase (HDAC) is an attractive target in liver fibrosis because it plays a key role in gene expression and cell differentiation. We have developed a HDAC inhibitor, N-hydroxy-7-(2-naphthylthio)heptanomide (HNHA), and investigated the anti-fibrotic activity of HNHA in vitro and in vivo. Experimental Approach We investigated the anti-fibrotic effect of HNHA on mouse and human HSC activation in vitro and in the liver of bile duct-ligated (BDL) rats in vivo using cell proliferation assays, cell cycle analysis, biochemical assay, immunohistochemistry and Western blots. Liver pathology was assessed with histochemical techniques. Key Results HNHA inhibited proliferation and arrested the cell cycle via p21 induction in HSCs. In addition, HNHA induced apoptosis of HSCs, which was correlated with reduced COX-2 expression, NF-?B activation and cell death signals. HNHA restored liver function and decreased the accumulation of extracellular matrix in the liver via suppression of HSC activation in BDL rats in vivo. HNHA administration also increased survival in BDL rats. Conclusions and Implications HNHA improved liver function, suppressed liver fibrosis and increased survival of BDL rats, accompanied by reduction of cell growth, activation and survival of HSCs. These findings show that HNHA may be a potent anti-fibrosis agent against hepatic fibrosis because of its multi-targeted inhibition of HSC activity in vivo and in vitro. PMID:24467283

Park, Ki Cheong; Park, Ji Hyun; Jeon, Jeong Yong; Kim, Sang Yong; Kim, Jung Min; Lim, Chang Yong; Lee, Tae Hyung; Kim, Hyung Kwan; Lee, Hyun Gyu; Kim, Sung Min; Kwon, Ho Jeong; Suh, Jin Suck; Kim, Seung Won; Choi, Seung Hoon

2014-01-01

291

The histone deacetylase inhibitor trichostatin A reduces lysosomal pH and enhances cisplatin-induced apoptosis.  

PubMed

High activity of histone deacetylases (HDACs) has been documented in several types of cancer and may be associated with survival advantage. In a head and neck squamous cell carcinoma cell line, cisplatin-induced apoptosis was augmented by pretreatment with the HDAC inhibitor trichostatin A. Apoptosis was accompanied by lysosomal membrane permeabilization (LMP), as shown by immunoblotting of the lysosomal marker protease cathepsin B in extracted cytosol and by immunofluorescence. Moreover, LAMP-2 (lysosomal associated membrane protein-2) was translocated from lysosomal membranes and found in a digitonin extractable fraction together with cytosolic proteins and pretreatment with trichostatin A potentiated the release. Overall, protein level of LAMP-2 was decreased during cell death and, interestingly, inhibition of cysteine cathepsins, by the pan-cysteine cathepsin inhibitor zFA-FMK, prevented loss of LAMP-2. The importance of LAMP-2 for lysosomal membrane stability, was confirmed by showing that LAMP-2 knockout MEFs (mouse embryonic fibroblasts) were more sensitive to cisplatin as compared to the corresponding wildtype cells. Trichostatin A reduced lysosomal pH from 4.46 to 4.25 and cell death was prevented when lysosomal pH was increased by NH(4)Cl, or when inhibiting the activity of lysosomal proteases. We conclude that trichostatin A enhances cisplatin induced cell death by decreasing lysosomal pH, which augments cathepsin activity resulting in reduced LAMP-2 level, and might promote LMP. PMID:23063877

Eriksson, I; Joosten, M; Roberg, K; Ollinger, K

2013-01-01

292

Activity of the histone deacetylase inhibitor belinostat (PXD101) in preclinical models of prostate cancer.  

PubMed

Histone deacetylase inhibitors (HDACi) represent a promising new class of anticancer agents. In the current investigation, we examined the activity of the HDACi belinostat in preclinical models of prostate cancer. In vitro proliferation assays demonstrated that belinostat potently inhibited the growth of prostate cancer cell lines (IC(50) < 1.0 microM) and was cytotoxic to these cells. Washout experiments indicated that exposure to belinostat for relatively short periods of time (<12 hr) induced suboptimal growth-inhibition and that cells exposed to 1.0 microM belinostat for 48 hr retained the capacity for regrowth following drug withdrawal, while cells exposed to 4.0 microM belinostat were irreversibly growth-inhibited. Cell cycle analyses demonstrated that belinostat induced G2/M arrest and increased the percentage of cells with subG1 DNA content, thus confirming the growth-inhibitory and cytotoxic effects of this compound. Normal prostate epithelial cells were generally less susceptible to the effects of belinostat than were prostate cancer cells. In an orthotopic prostate cancer tumor model, belinostat inhibited tumor growth by up to 43%. Moreover, metastatic lung lesions were present in 47% of vehicle-treated animals but in none of the animals administered belinostat. Consistent with its observed antimetastatic activity, belinostat inhibited the migration of prostate tumor cells and increased the production of tissue inhibitor of metalloproteinase-1 (TIMP-1) by these cells, the latter effect being replicated by siRNA knockdown of HDAC3. Belinostat also increased the expression of p21 and decreased the expression of potentially oncogenic proteins (mutant p53 and ERG). These results support the clinical evaluation of belinostat for the treatment of prostate cancer. PMID:18027850

Qian, Xiaozhong; Ara, Gulshan; Mills, Evan; LaRochelle, William J; Lichenstein, Henri S; Jeffers, Michael

2008-03-15

293

Histone deacetylase inhibitors prevent the degradation and restore the activity of glucocerebrosidase in Gaucher disease  

PubMed Central

Gaucher disease (GD) is caused by a spectrum of genetic mutations within the gene encoding the lysosomal enzyme glucocerebrosidase (GCase). These mutations often lead to misfolded proteins that are recognized by the unfolded protein response system and are degraded through the ubiquitin–proteasome pathway. Modulating this pathway with histone deacetylase inhibitors (HDACis) has been shown to improve protein stability in other disease settings. To identify the mechanisms involved in the regulation of GCase and determine the effects of HDACis on protein stability, we investigated the most prevalent mutations for nonneuronopathic (N370S) and neuronopathic (L444P) GD in cultured fibroblasts derived from GD patients and HeLa cells transfected with these mutations. The half-lives of mutant GCase proteins correspond to decreases in protein levels and enzymatic activity. GCase was found to bind to Hsp70, which directed the protein to TCP1 for proper folding, and to Hsp90, which directed the protein to the ubiquitin–proteasome pathway. Using a known HDACi (SAHA) and a unique small-molecule HDACi (LB-205), GCase levels increased rescuing enzymatic activity in mutant cells. The increase in the quantity of protein can be attributed to increases in protein half-life that correspond primarily with a decrease in degradation rather than an increase in chaperoned folding. HDACis reduce binding to Hsp90 and prevent subsequent ubiquitination and proteasomal degradation without affecting binding to Hsp70 or TCP1. These findings provide insight into the pathogenesis of GD and indicate a potent therapeutic potential of HDAC inhibitors for the treatment of GD and other human protein misfolding disorders. PMID:22160715

Lu, Jie; Yang, Chunzhang; Chen, Masako; Ye, Donald Y.; Lonser, Russell R.; Brady, Roscoe O.; Zhuang, Zhengping

2011-01-01

294

HDAC inhibitors and immunotherapy; a double edged sword?  

PubMed Central

Epigenetic modifications, like histone acetylation, are essential for regulating gene expression within cells. Cancer cells acquire pathological epigenetic modifications resulting in gene expression patterns that facilitate and sustain tumorigenesis. Epigenetic manipulation therefore is emerging as a novel targeted therapy for cancer. Histone Acetylases (HATs) and Histone Deacetylases (HDACs) regulate histone acetylation and hence gene expression. Histone deacetylase (HDAC) inhibitors are well known to affect cancer cell viability and biology and are already in use for the treatment of cancer patients. Immunotherapy can lead to clinical benefit in selected cancer patients, especially in patients with limited disease after tumor debulking. HDAC inhibitors can potentially synergize with immunotherapy by elimination of tumor cells. The direct effects of HDAC inhibitors on immune cell function, however, remain largely unexplored. Initial data have suggested HDAC inhibitors to be predominantly immunosuppressive, but more recent reports have challenged this view. In this review we will discuss the effects of HDAC inhibitors on tumor cells and different immune cell subsets, synergistic interactions and possible mechanisms. Finally, we will address future challenges and potential application of HDAC inhibitors in immunocombination therapy of cancer. PMID:25115382

Kroesen, Michiel; Armandari, Inna; Hoogerbrugge, Peter M.; Adema, Gosse J.

2014-01-01

295

Combination Therapy: Histone Deacetylase Inhibitors and Platinum-based Chemotherapeutics for Cancer  

PubMed Central

One of the most promising strategies to increase the efficacy of standard chemotherapy drugs is by combining them with low doses of histone deacetylases inhibitors (HDACis). Regarded as chemosensitizers, the addition of well-tolerated doses of HDACis to platinum-based chemotherapeutics has been proven in vitro and in vivo in recent studies for many cancer types and stages. In this review, we discuss the most commonly used combinations of histone deacetylase inhibitors and platinum based drugs in the context of their possible mechanisms, efficiency, efficacy, and related drawbacks in preclinical and clinical studies. PMID:23032720

Diyabalanage, Himashinie V. K.; Granda, Michael L.; Hooker, Jacob M.

2012-01-01

296

Anticancer Activity of MPT0E028, a Novel Potent Histone Deacetylase Inhibitor, in Human Colorectal Cancer HCT116 Cells In Vitro and In Vivo  

PubMed Central

Recently, histone deacetylase (HDAC) inhibitors have emerged as a promising class of drugs for treatment of cancers, especially subcutaneous T-cell lymphoma. In this study, we demonstrated that MPT0E028, a novel N-hydroxyacrylamide-derived HDAC inhibitor, inhibited human colorectal cancer HCT116 cell growth in vitro and in vivo. The results of NCI-60 screening showed that MPT0E028 inhibited proliferation in both solid and hematological tumor cell lines at micromolar concentrations, and was especially potent in HCT116 cells. MPT0E028 had a stronger apoptotic activity and inhibited HDACs activity more potently than SAHA, the first therapeutic HDAC inhibitor proved by FDA. In vivo murine model, the growth of HCT116 tumor xenograft was delayed and inhibited after treatment with MPT0E028 in a dose-dependent manner. Based on in vivo study, MPT0E028 showed stronger anti-cancer efficacy than SAHA. No significant body weight difference or other adverse effects were observed in both MPT0E028-and SAHA-treated groups. Taken together, our results demonstrate that MPT0E028 has several properties and is potential as a promising anti-cancer therapeutic drug. PMID:22928010

Tsai, An-Chi; Peng, Chieh-Yu; Lai, Mei-Jung; Wang, Jing-Chi; Pan, Shiow-Lin; Teng, Che-Ming; Liou, Jing-Ping

2012-01-01

297

Utilization of Boron Compounds for the Modification of Suberoyl Anilide Hydroxamic Acid as Inhibitor of Histone Deacetylase Class II Homo sapiens  

PubMed Central

Histone deacetylase (HDAC) has a critical function in regulating gene expression. The inhibition of HDAC has developed as an interesting anticancer research area that targets biological processes such as cell cycle, apoptosis, and cell differentiation. In this study, an HDAC inhibitor that is available commercially, suberoyl anilide hydroxamic acid (SAHA), has been modified to improve its efficacy and reduce the side effects of the compound. Hydrophobic cap and zinc-binding group of these compounds were substituted with boron-based compounds, whereas the linker region was substituted with p-aminobenzoic acid. The molecular docking analysis resulted in 8 ligands with ?Gbinding value more negative than the standards, SAHA and trichostatin A (TSA). That ligands were analyzed based on the nature of QSAR, pharmacological properties, and ADME-Tox. It is conducted to obtain a potent inhibitor of HDAC class II Homo sapiens. The screening process result gave one best ligand, Nova2 (513246-99-6), which was then further studied by molecular dynamics simulations. PMID:25214833

Bakri, Ridla; Parikesit, Arli Aditya; Satriyanto, Cipta Prio; Kerami, Djati; Tambunan, Usman Sumo Friend

2014-01-01

298

Synthesis, bioevaluation and docking study of 5-substitutedphenyl-1,3,4-thiadiazole-based hydroxamic acids as histone deacetylase inhibitors and antitumor agents.  

PubMed

Since the first histone deacetylase (HDAC) inhibitor (Zolinza®, widely known as suberoylanilide hydroxamic acid; SAHA) was approved by the Food and Drug Administration for the treatment of T-cell lymphoma in 2006, the search for newer HDAC inhibitors has attracted a great deal of interest of medicinal chemists worldwide. As a continuity of our ongoing research in this area, we designed and synthesized a series of 5-substitutedphenyl-1,3,4-thiadiazole-based hydroxamic acids as analogues of SAHA and evaluated their biological activities. A number of compounds in this series, for example, N(1)-hydroxy-N(8)-(5-(2-chlorophenyl)-1,3,4-thiadiazol-2-yl)octandiamide (5b), N(1)-hydroxy-N(8)-(5-(3-chlorophenyl-1,3,4-thiadiazol-2-yl)octandiamide (5c) and N(1)-hydroxy-N(8)-(5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl)octandiamide (5d), were found to possess potent anticancer cytotoxicity and HDAC inhibition effects. Compounds 5b-d were generally two- to five-fold more potent in terms of cytotoxicity compared to SAHA against five cancer cell lines tested. Docking studies revealed that these hydroxamic acid displayed higher affinities than SAHA toward HDAC8. PMID:24020585

Nam, Nguyen-Hai; Huong, Tran Lan; Dung, Do Thi Mai; Dung, Phan Thi Phuong; Oanh, Dao Thi Kim; Park, Sang Ho; Kim, Kyungrok; Han, Byung Woo; Yun, Jieun; Kang, Jong Soon; Kim, Youngsoo; Han, Sang-Bae

2014-10-01

299

Histone deacetylase 6–mediated selective autophagy regulates COPD-associated cilia dysfunction  

PubMed Central

Chronic obstructive pulmonary disease (COPD) involves aberrant airway inflammatory responses to cigarette smoke (CS) that are associated with epithelial cell dysfunction, cilia shortening, and mucociliary clearance disruption. Exposure to CS reduced cilia length and induced autophagy in vivo and in differentiated mouse tracheal epithelial cells (MTECs). Autophagy-impaired (Becn1+/– or Map1lc3B–/–) mice and MTECs resisted CS-induced cilia shortening. Furthermore, CS increased the autophagic turnover of ciliary proteins, indicating that autophagy may regulate cilia homeostasis. We identified cytosolic deacetylase HDAC6 as a critical regulator of autophagy-mediated cilia shortening during CS exposure. Mice bearing an X chromosome deletion of Hdac6 (Hdac6–/Y) and MTECs from these mice had reduced autophagy and were protected from CS-induced cilia shortening. Autophagy-impaired Becn1–/–, Map1lc3B–/–, and Hdac6–/Y mice or mice injected with an HDAC6 inhibitor were protected from CS-induced mucociliary clearance (MCC) disruption. MCC was preserved in mice given the chemical chaperone 4-phenylbutyric acid, but was disrupted in mice lacking the transcription factor NRF2, suggesting that oxidative stress and altered proteostasis contribute to the disruption of MCC. Analysis of human COPD specimens revealed epigenetic deregulation of HDAC6 by hypomethylation and increased protein expression in the airways. We conclude that an autophagy-dependent pathway regulates cilia length during CS exposure and has potential as a therapeutic target for COPD. PMID:24200693

Lam, Hilaire C.; Cloonan, Suzanne M.; Bhashyam, Abhiram R.; Haspel, Jeffery A.; Singh, Anju; Sathirapongsasuti, J. Fah; Cervo, Morgan; Yao, Hongwei; Chung, Anna L.; Mizumura, Kenji; An, Chang Hyeok; Shan, Bin; Franks, Jonathan M.; Haley, Kathleen J.; Owen, Caroline A.; Tesfaigzi, Yohannes; Washko, George R.; Quackenbush, John; Silverman, Edwin K.; Rahman, Irfan; Kim, Hong Pyo; Mahmood, Ashfaq; Biswal, Shyam S.; Ryter, Stefan W.; Choi, Augustine M.K.

2013-01-01

300

Dual Regulation by Pairs of Cyclin-Dependent Protein Kinases and Histone Deacetylases Controls G1 Transcription in Budding Yeast  

PubMed Central

START-dependent transcription in Saccharomyces cerevisiae is regulated by two transcription factors SBF and MBF, whose activity is controlled by the binding of the repressor Whi5. Phosphorylation and removal of Whi5 by the cyclin-dependent kinase (CDK) Cln3-Cdc28 alleviates the Whi5-dependent repression on SBF and MBF, initiating entry into a new cell cycle. This Whi5-SBF/MBF transcriptional circuit is analogous to the regulatory pathway in mammalian cells that features the E2F family of G1 transcription factors and the retinoblastoma tumor suppressor protein (Rb). Here we describe genetic and biochemical evidence for the involvement of another CDK, Pcl-Pho85, in regulating G1 transcription, via phosphorylation and inhibition of Whi5. We show that a strain deleted for both PHO85 and CLN3 has a slow growth phenotype, a G1 delay, and is severely compromised for SBF-dependent reporter gene expression, yet all of these defects are alleviated by deletion of WHI5. Our biochemical and genetic tests suggest Whi5 mediates repression in part through interaction with two histone deacetylases (HDACs), Hos3 and Rpd3. In a manner analogous to cyclin D/CDK4/6, which phosphorylates Rb in mammalian cells disrupting its association with HDACs, phosphorylation by the early G1 CDKs Cln3-Cdc28 and Pcl9-Pho85 inhibits association of Whi5 with the HDACs. Contributions from multiple CDKs may provide the precision and accuracy necessary to activate G1 transcription when both internal and external cues are optimal. PMID:19823668

van Dyk, Dewald; Friesen, Helena; Sopko, Richelle; Ye, Wei; Bastajian, Nazareth; Moffat, Jason; Sassi, Holly; Costanzo, Michael; Andrews, Brenda J.

2009-01-01

301

Histone Deacetylase Inhibition Rescues Gene Knockout Levels Achieved with Integrase-Defective Lentiviral Vectors Encoding Zinc-Finger Nucleases  

PubMed Central

Abstract Zinc-finger nucleases (ZFNs) work as dimers to induce double-stranded DNA breaks (DSBs) at predefined chromosomal positions. In doing so, they constitute powerful triggers to edit and to interrogate the function of genomic sequences in higher eukaryotes. A preferred route to introduce ZFNs into somatic cells relies on their cotransduction with two integrase-defective lentiviral vectors (IDLVs) each encoding a monomer of a functional heterodimeric pair. The episomal nature of IDLVs diminishes the risk of genotoxicity and ensures the strict transient expression profile necessary to minimize deleterious effects associated with long-term ZFN activity. However, by deploying IDLVs and conventional lentiviral vectors encoding HPRT1- or eGFP-specific ZFNs, we report that DSB formation at target alleles is limited after IDLV-mediated ZFN transfer. This IDLV-specific underperformance stems, to a great extent, from the activity of chromatin-remodeling histone deacetylases (HDACs). Importantly, the prototypic and U.S. Food and Drug Administration–approved inhibitors of metal-dependent HDACs, trichostatin A and vorinostat, respectively, did not hinder illegitimate recombination-mediated repair of targeted chromosomal DSBs. This allowed rescuing IDLV-mediated site-directed mutagenesis to levels approaching those achieved by using their isogenic chromosomally integrating counterparts. Hence, HDAC inhibition constitutes an efficacious expedient to incorporate in genome-editing strategies based on transient IDLV-mediated ZFN expression. Finally, we compared two of the most commonly used readout systems to measure targeted gene knockout activities based on restriction and mismatch-sensitive endonucleases. These experiments indicate that these enzymatic assays display a similar performance. PMID:24059449

Pelascini, Laetitia P.L.; Maggio, Ignazio; Liu, Jin; Holkers, Maarten; Cathomen, Toni

2013-01-01

302

An “Exacerbate-reverse” Strategy in Yeast Identifies Histone Deacetylase Inhibition as a Correction for Cholesterol and Sphingolipid Transport Defects in Human Niemann-Pick Type C Disease*?  

PubMed Central

Niemann-Pick type C (NP-C) disease is a fatal lysosomal lipid storage disorder for which no effective therapy exists. A genome-wide, conditional synthetic lethality screen was performed using the yeast model of NP-C disease during anaerobiosis, an auxotrophic condition that requires yeast to utilize exogenous sterol. We identified 12 pathways and 13 genes as modifiers of the absence of the yeast NPC1 ortholog (NCR1) and quantified the impact of loss of these genes on sterol metabolism in ncr1? strains grown under viable aerobic conditions. Deletion of components of the yeast NuA4 histone acetyltransferase complex in ncr1? strains conferred anaerobic inviability and accumulation of multiple sterol intermediates. Thus, we hypothesize an imbalance in histone acetylation in human NP-C disease. Accordingly, we show that the majority of the 11 histone deacetylase (HDAC) genes are transcriptionally up-regulated in three genetically distinct fibroblast lines derived from patients with NP-C disease. A clinically approved HDAC inhibitor (suberoylanilide hydroxamic acid) reverses the dysregulation of the majority of the HDAC genes. Consequently, three key cellular diagnostic criteria of NP-C disease are dramatically ameliorated as follows: lysosomal accumulation of both cholesterol and sphingolipids and defective esterification of LDL-derived cholesterol. These data suggest HDAC inhibition as a candidate therapy for NP-C disease. We conclude that pathways that exacerbate lethality in a model organism can be reversed in human cells as a novel therapeutic strategy. This “exacerbate-reverse” approach can potentially be utilized in any model organism for any disease. PMID:21489983

Munkacsi, Andrew B.; Chen, Fannie W.; Brinkman, Matthew A.; Higaki, Katsumi; Gutiérrez, Giselle Domínguez; Chaudhari, Jagruti; Layer, Jacob V.; Tong, Amy; Bard, Martin; Boone, Charles; Ioannou, Yiannis A.; Sturley, Stephen L.

2011-01-01

303

Histone deacetylase inhibitors activate CIITA and MHC class II antigen expression in diffuse large B-cell lymphoma  

PubMed Central

Diffuse large B-cell lymphoma (DLBCL), the most common form of non-Hodgkin's lymphoma (NHL) diagnosed in the USA, consists of at least two distinct subtypes: germinal centre B (GCB) and activated B-cell (ABC). Decreased MHC class II (MHCII) expression on the tumours in both DLBCL subtypes directly correlates with significant decreases in patient survival. One common mechanism accounting for MHCII down-regulation in DLBCL is reduced expression of the MHC class II transactivator (CIITA), the master regulator of MHCII transcription. Furthermore, reduced CIITA expression in ABC DLBCL correlates with the presence of the transcriptional repressor positive regulatory domain-I-binding factor-1 (PRDI-BF1). However, the mechanisms underlying down-regulation of CIITA in GCB DLBCL are currently unclear. In this study, we demonstrate that neither PRDI-BF1 nor CpG hypermethylation at the CIITA promoters are responsible for decreased CIITA in GCB DLBCL. In contrast, histone modifications associated with an open chromatin conformation and active transcription were significantly lower at the CIITA promoters in CIITA? GCB cells compared with CIITA+ B cells, which suggests that epigenetic mechanisms contribute to repression of CIITA transcription. Treatment of CIITA? or CIITAlow GCB cells with several different histone deacetylase inhibitors (HDACi) activated modest CIITA and MHCII expression. However, CIITA and MHCII levels were significantly higher in these cells after exposure to the HDAC-1-specific inhibitor MS-275. These results suggest that CIITA transcription is repressed in GCB DLBCL cells through epigenetic mechanisms involving HDACs, and that HDACi treatment can alleviate repression. These observations may have important implications for patient therapy. PMID:23789844

Cycon, Kelly A; Mulvaney, Kathleen; Rimsza, Lisa M; Persky, Daniel; Murphy, Shawn P

2013-01-01

304

Fluorescence-Based Screening Assays for the NAD+-Dependent Histone Deacetylase smSirt2 from Schistosoma mansoni.  

PubMed

Sirtuins are NAD(+)-dependent histone deacetylases (HDACs) that cleave off acetyl but also other acyl groups from the ?-amino group of lysines in histones and other substrate proteins. Five sirtuin isoforms are encoded in the genome of the parasitic pathogen Schistosoma mansoni. During its life cycle, S. mansoni undergoes drastic changes in phenotype that are associated with epigenetic modifications. Previous work showed strong effects of hSirt2 inhibitors on both worm life span and reproduction. Thus, we postulate smSirt2 as a new antiparasite target. We report both the optimization of a homogeneous fluorescence-based assay and the development of a new heterogeneous fluorescence-based assay to determine smSirt2 activity. The homogeneous assay uses a coumarin-labeled acetyl lysine derivative, and the heterogeneous version is using a biotinylated and fluorescence-labeled oligopeptide. Magnetic streptavidin-coated beads allow higher substrate loading per well than streptavidin-coated microtiter plates and make it possible to screen for inhibitors of either smSirt2 or its human isoform (hSirt2) for selectivity studies. We also present hits from a pilot screen with inhibitors showing an IC50 lower than 50 µM. Binding of the hits to their targets is rationalized by docking studies using a homology model of smSirt2. PMID:25325257

Schiedel, Matthias; Marek, Martin; Lancelot, Julien; Karaman, Berin; Almlöf, Ingrid; Schultz, Johan; Sippl, Wolfgang; Pierce, Raymond J; Romier, Christophe; Jung, Manfred

2015-01-01

305

Regulation of Small Ubiquitin-Like Modifier-1, Nuclear Receptor Coreceptor, Histone Deacetylase 3, and Peroxisome Proliferator-Activated Receptor-? in Human Adipose Tissue  

PubMed Central

Abstract Background This study investigated the regulation of peroxisome proliferator-activated receptor-? (PPAR?), the histone deacetylase 3 (HDAC3)–nuclear receptor coreceptor (NCoR) complex (a corepressor of transcription used by PPAR?), and small ubiquitin-like modifier-1 (SUMO-1) (a posttranslational modifier of PPAR?) in human adipose tissue and both adipocyte and macrophage cell lines. The objective was to determine whether there were alterations in the human adipose tissue gene expression levels of PPAR?, HDAC3, NCoR, and SUMO-1 associated either with obesity or with treatment of impaired glucose tolerance (IGT) subjects with insulin-sensitizing medications. Methods We obtained subcutaneous adipose tissue biopsies from 86 subjects with a wide range of body mass index (BMI) and insulin sensitivity (SI). Additionally, adipose tissue biopsies were obtained from a randomized subgroup of IGT subjects before and after 10 weeks of treatment with either pioglitazone or metformin. Results The adipose mRNA levels of PPAR?, NCoR, HDAC3, and SUMO-1 correlated strongly with each other (P<0.0001); however, SUMO-1, NCoR, and HDAC3 gene expression were not significantly associated with BMI or SI. Pioglitazone increased SUMO-1 expression by 23% (P<0.002) in adipose tissue and an adipocyte cell line (P<0.05), but not in macrophages. Small interfering RNA (siRNA)-mediated knockdown of SUMO-1 decreased PPAR?, HDAC3, and NCoR in THP-1 cells and increased tumor necrosis factor-? (TNF-?) induction in response to lipopolysaccharide (LPS). Conclusions These results suggest that the coordinate regulation of SUMO-1, PPAR?1/2, HDAC3, and NCoR may be more tightly controlled in macrophages than in adipocytes in human adipose and that these modulators of PPAR? activity may be particularly important in the negative regulation of macrophage-mediated adipose inflammation by pioglitazone. PMID:22651256

Bodles-Brakhop, Angela M.; Yao-Borengasser, Aiwei; Zhu, Beibei; Starnes, Catherine P.; McGehee, Robert E.; Peterson, Charlotte A.; Kern, Philip A.

2012-01-01

306

Requirement of Hos2 Histone Deacetylase for Gene Activity in Yeast  

Microsoft Academic Search

Histone deacetylases, typified by class I Rpd3 in the yeast Saccharomyces cerevisiae, have historically been associated with gene repression. We now demonstrate that Hos2, another member of the class I family, binds to the coding regions of genes primarily during gene activation, when it specifically deacetylates the lysines in H3 and H4 histone tails. Moreover, Hos2 is preferentially associated with

Amy Wang; Siavash K. Kurdistani; Michael Grunstein

2002-01-01

307

Histone Deacetylase Inhibitor Romidepsin Induces HIV Expression in CD4 T Cells from Patients on Suppressive Antiretroviral Therapy at Concentrations Achieved by Clinical Dosing  

PubMed Central

Persistent latent reservoir of replication-competent proviruses in memory CD4 T cells is a major obstacle to curing HIV infection. Pharmacological activation of HIV expression in latently infected cells is being explored as one of the strategies to deplete the latent HIV reservoir. In this study, we characterized the ability of romidepsin (RMD), a histone deacetylase inhibitor approved for the treatment of T-cell lymphomas, to activate the expression of latent HIV. In an in vitro T-cell model of HIV latency, RMD was the most potent inducer of HIV (EC50?=?4.5 nM) compared with vorinostat (VOR; EC50?=?3,950 nM) and other histone deacetylase (HDAC) inhibitors in clinical development including panobinostat (PNB; EC50?=?10 nM). The HIV induction potencies of RMD, VOR, and PNB paralleled their inhibitory activities against multiple human HDAC isoenzymes. In both resting and memory CD4 T cells isolated from HIV-infected patients on suppressive combination antiretroviral therapy (cART), a 4-hour exposure to 40 nM RMD induced a mean 6-fold increase in intracellular HIV RNA levels, whereas a 24-hour treatment with 1 µM VOR resulted in 2- to 3-fold increases. RMD-induced intracellular HIV RNA expression persisted for 48 hours and correlated with sustained inhibition of cell-associated HDAC activity. By comparison, the induction of HIV RNA by VOR and PNB was transient and diminished after 24 hours. RMD also increased levels of extracellular HIV RNA and virions from both memory and resting CD4 T-cell cultures. The activation of HIV expression was observed at RMD concentrations below the drug plasma levels achieved by doses used in patients treated for T-cell lymphomas. In conclusion, RMD induces HIV expression ex vivo at concentrations that can be achieved clinically, indicating that the drug may reactivate latent HIV in patients on suppressive cART. PMID:24722454

Wei, Datsen George; Chiang, Vicki; Fyne, Elizabeth; Balakrishnan, Mini; Barnes, Tiffany; Graupe, Michael; Hesselgesser, Joseph; Irrinki, Alivelu; Murry, Jeffrey P.; Stepan, George; Stray, Kirsten M.; Tsai, Angela; Yu, Helen; Spindler, Jonathan; Kearney, Mary; Spina, Celsa A.; McMahon, Deborah; Lalezari, Jacob; Sloan, Derek; Mellors, John; Geleziunas, Romas; Cihlar, Tomas

2014-01-01

308

Real-time gene expression analysis in human xenografts for evaluation of histone deacetylase inhibitors.  

PubMed

Real-time analysis of gene expression in experimental tumor models represents a major tool to document disease biology and evaluate disease treatment. However, monitoring gene regulation in vivo still is an emerging field, and thus far it has not been linked to long-term tumor growth and disease outcome. In this report, we describe the development and validation of a fluorescence-based gene expression model driven by the promoter of the cyclin-dependent kinase inhibitor p21waf1,cip1. The latter is a key regulator of tumor cell proliferation and a major determinant in the response to many anticancer agents such as histone deacetylase inhibitors. In response to histone deacetylase inhibitors, induction of fluorescence in A2780 ovarian tumors could be monitored in living mice in a noninvasive real-time manner using whole-body imaging. Single p.o. administration of the histone deacetylase inhibitor MS-275 significantly induces tumor fluorescence in a time- and dose-dependent manner, which accurately predicted long-term antitumoral efficacy in individual mice following extended treatment. These findings illustrate that this technology allows monitoring of the biological response induced by treatment with histone deacetylase inhibitors. In addition to providing experimental pharmacokinetic/pharmacodynamic markers for investigational drugs, this model provides insight into the kinetics of in vivo regulation of transcription, which plays a key role in causing and maintaining the uncontrolled proliferation of tumor tissue. PMID:16985066

Beliën, Ann; De Schepper, Stefanie; Floren, Wim; Janssens, Boud; Mariën, Ann; King, Peter; Van Dun, Jacky; Andries, Luc; Voeten, Jan; Bijnens, Luc; Janicot, Michel; Arts, Janine

2006-09-01

309

Distinct roles of HDAC complexes in promoter silencing, antisense suppression and DNA damage protection  

Microsoft Academic Search

Histone acetylation is important in regulating DNA accessibility. Multifunctional Sin3 proteins bind histone deacetylases (HDACs) to assemble silencing complexes that selectively target chromatin. We show that, in fission yeast, an essential HDAC, Clr6, exists in two distinct Sin3 core complexes. Complex I contains an essential Sin3 homolog, Pst1, and other factors, and predominantly targets gene promoters. Complex II contains a

Estelle Nicolas; Takatomi Yamada; Hugh P Cam; Peter C FitzGerald; Ryuji Kobayashi; Shiv I S Grewal

2007-01-01

310

In vivo destabilization of dynamic microtubules by HDAC6-mediated deacetylation  

PubMed Central

Trichostatin A (TSA) inhibits all histone deacetylases (HDACs) of both class I and II, whereas trapoxin (TPX) cannot inhibit HDAC6, a cytoplasmic member of class II HDACs. We took advantage of this differential sensitivity of HDAC6 to TSA and TPX to identify its substrates. Using this approach, ?-tubulin was identified as an HDAC6 substrate. HDAC6 deacetylated ?-tubulin both in vivo and in vitro. Our investigations suggest that HDAC6 controls the stability of a dynamic pool of microtubules. Indeed, we found that highly acetylated microtubules observed after TSA treatment exhibited delayed drug-induced depolymerization and that HDAC6 overexpression prompted their induced depolymerization. Depolymerized tubulin was rapidly deacetylated in vivo, whereas tubulin acetylation occurred only after polymerization. We therefore suggest that acetylation and deacetylation are coupled to the microtubule turnover and that HDAC6 plays a key regulatory role in the stability of the dynamic microtubules. PMID:12486003

Matsuyama, Akihisa; Shimazu, Tadahiro; Sumida, Yuko; Saito, Akiko; Yoshimatsu, Yasuhiro; Seigneurin-Berny, Daphné; Osada, Hiroyuki; Komatsu, Yasuhiko; Nishino, Norikazu; Khochbin, Saadi; Horinouchi, Sueharu; Yoshida, Minoru

2002-01-01

311

HDAC4 blocks autophagy to trigger podocyte injury: non-epigenetic action in diabetic nephropathy.  

PubMed

Histone deacetylases (HDACs) have been implicated in the pathogenesis of kidney diseases including diabetic nephropathy (DN); however, the mechanism is poorly understood. Wang et al. unravel the changes in expression of various HDACs in DN and demonstrate that HDAC4 specifically contributes to podocyte injury in DN. HDAC4 deacetylates STAT1 to suppress autophagy, an essential cellular process for the function and viability of podocytes. The development of HDAC isoform-specific inhibitors may provide efficacious therapeutics for DN and related renal diseases. PMID:25265947

Wei, Qingqing; Dong, Zheng

2014-10-01

312

Quantitative Analysis of Histone Modifications: Formaldehyde Is a Source of Pathological N6-Formyllysine That Is Refractory to Histone Deacetylases  

PubMed Central

Aberrant protein modifications play an important role in the pathophysiology of many human diseases, in terms of both dysfunction of physiological modifications and the formation of pathological modifications by reaction of proteins with endogenous electrophiles. Recent studies have identified a chemical homolog of lysine acetylation, N6-formyllysine, as an abundant modification of histone and chromatin proteins, one possible source of which is the reaction of lysine with 3?-formylphosphate residues from DNA oxidation. Using a new liquid chromatography-coupled to tandem mass spectrometry method to quantify all N6-methyl-, -acetyl- and -formyl-lysine modifications, we now report that endogenous formaldehyde is a major source of N6-formyllysine and that this adduct is widespread among cellular proteins in all compartments. N6-formyllysine was evenly distributed among different classes of histone proteins from human TK6 cells at 1–4 modifications per 104 lysines, which contrasted strongly with lysine acetylation and mono-, di-, and tri-methylation levels of 1.5-380, 5-870, 0-1400, and 0-390 per 104 lysines, respectively. While isotope labeling studies revealed that lysine demethylation is not a source of N6-formyllysine in histones, formaldehyde exposure was observed to cause a dose-dependent increase in N6-formyllysine, with use of [13C,2H2]-formaldehyde revealing unchanged levels of adducts derived from endogenous sources. Inhibitors of class I and class II histone deacetylases did not affect the levels of N6-formyllysine in TK6 cells, and the class III histone deacetylase, SIRT1, had minimal activity (<10%) with a peptide substrate containing the formyl adduct. These data suggest that N6-formyllysine is refractory to removal by histone deacetylases, which supports the idea that this abundant protein modification could interfere with normal regulation of gene expression if it arises at conserved sites of physiological protein secondary modification. PMID:23468656

Edrissi, Bahar; Taghizadeh, Koli; Dedon, Peter C.

2013-01-01

313

HDAC3 is a negative regulator of cocaine-context associated memory formation  

PubMed Central

Cocaine-induced neuroplasticity mediated by histone acetylating and deacetylating enzymes may contribute to addiction-like behaviors. For example, over expression of histone deacetylases (HDACs) 4 or 5 in the nucleus accumbens (NAc) suppresses cocaine-induced conditioned place preference (CPP) acquisition in mice. HDAC4 and HDAC5 are known to interact with HDAC3, but the role of HDAC3 in cocaine-induced behaviors has never been examined. In this study, we address the hypothesis that HDAC3 is a negative regulator of cocaine-context associated memory formation in mice. We examined the role of HDAC3 during the conditioning phase of CPP, when the mouse has the opportunity to form an associative memory between the cocaine-paired context and the subjective effects of cocaine. To address this hypothesis, Hdac3flox/flox and Hdac3+/+ mice (generated from a C57B/L6 background) were infused intra-NAc with AAV-Cre recombinase to create focal, homozygous Hdac3 deletions. Hdac3flox/flox mice exhibit significantly enhanced CPP acquisition, which correlates with increased gene expression during the consolidation phase of acquisition. Increased gene expression of c-Fos and Nr4a2 correlated with decreased HDAC3 occupancy and increased histone H4 lysine 8 (H4K8) acetylation at their promoters. Together, results from this study demonstrate that HDAC3 negatively regulates cocaine-induced CPP acquisition. PMID:23575859

Rogge, George A.; Singh, Harsimran; Dang, Richard; Wood, Marcelo A.

2013-01-01

314

A novel histone deacetylase inhibitor, CG0006, induces cell death through both extrinsic and intrinsic apoptotic pathways.  

PubMed

Histone deacetylase inhibitors (HDACIs) are potent anticancer drugs, and suberoylanilide hydroxamic acid is used for the treatment of cutaneous T-cell lymphoma patients. We synthesized a novel hydroxamate-based HDACI, CG0006, and assessed its antiproliferative effects on the NCI-60 cancer cell panel and cell lines from liver and stomach cancers that are common in Korea. Micromolar levels of CG0006 induced cell death in several breast, central nervous system, colon, hematopoietic, lung, melanoma, ovarian, prostatic, renal, and stomach cancer cell lines. We further analyzed cell death mechanisms activated by CG0006 in HCT116 (colon cancer) and K562 (leukemia) cells. First, to test the activity of CG0006, we analyzed acetylation of substrates of HDACs and effect on gene expression. CG0006 increased acetylation of histone 3, histone 4, and tubulin in a time-dependent and dose-dependent manner in both HCT116 and K562 cells. Moreover, CG0006 increased the mRNA level of p21 and decreased that of Bcl-xl efficiently in HCT116 cells. Cell cycle analysis showed G2-M arrest, and increased apoptosis in populations of HCT116 and K562 cells treated with CG0006. Western blot analysis showed that CG0006 increased levels of p21 in HCT116 cells and of p21 and p27 in K562 cells. In addition, CG0006 activated caspase-9, caspase-3, and caspase-8. These results indicate that CG0006 induces death in HCT116 and K562 cells through both intrinsic and extrinsic apoptotic pathways. The HDACI CG0006 may be a potent anticancer drug for solid tumors and leukemia. PMID:19644355

Hwang, Jung Jin; Kim, Yong Sook; Kim, Mi Joung; Jang, Sejin; Lee, Je-Hwan; Choi, Jene; Ro, Seonggu; Hyun, Young-Lan; Lee, Jung Shin; Kim, Choung-Soo

2009-10-01

315

Blockade of the ERK pathway enhances the therapeutic efficacy of the histone deacetylase inhibitor MS-275 in human tumor xenograft models  

SciTech Connect

Highlights: •Blockade of the ERK pathway enhances the anticancer efficacy of HDAC inhibitors. •MEK inhibitors sensitize human tumor xenografts to HDAC inhibitor cytotoxicity. •Such the enhanced efficacy is achieved by a transient blockade of the ERK pathway. •This drug combination provides a promising therapeutic strategy for cancer patients. -- Abstract: The ERK pathway is up-regulated in various human cancers and represents a prime target for mechanism-based approaches to cancer treatment. Specific blockade of the ERK pathway alone induces mostly cytostatic rather than pro-apoptotic effects, however, resulting in a limited therapeutic efficacy of the ERK kinase (MEK) inhibitors. We previously showed that MEK inhibitors markedly enhance the ability of histone deacetylase (HDAC) inhibitors to induce apoptosis in tumor cells with constitutive ERK pathway activation in vitro. To evaluate the therapeutic efficacy of such drug combinations, we administered the MEK inhibitor PD184352 or AZD6244 together with the HDAC inhibitor MS-275 in nude mice harboring HT-29 or H1650 xenografts. Co-administration of the MEK inhibitor markedly sensitized the human xenografts to MS-275 cytotoxicity. A dose of MS-275 that alone showed only moderate cytotoxicity thus suppressed the growth of tumor xenografts almost completely as well as induced a marked reduction in tumor cellularity when administered with PD184352 or AZD6244. The combination of the two types of inhibitor also induced marked oxidative stress, which appeared to result in DNA damage and massive cell death, specifically in the tumor xenografts. The enhanced therapeutic efficacy of the drug combination was achieved by a relatively transient blockade of the ERK pathway. Administration of both MEK and HDAC inhibitors represents a promising chemotherapeutic strategy with improved safety for cancer patients.

Sakamoto, Toshiaki; Ozaki, Kei-ichi; Fujio, Kohsuke; Kajikawa, Shu-hei [Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521 (Japan)] [Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521 (Japan); Uesato, Shin-ichi [Department of Biotechnology, Faculty of Engineering, Kansai University, Osaka 564-8680 (Japan)] [Department of Biotechnology, Faculty of Engineering, Kansai University, Osaka 564-8680 (Japan); Watanabe, Kazushi [Proubase Technology Inc., Kanagawa 211-0063 (Japan)] [Proubase Technology Inc., Kanagawa 211-0063 (Japan); Tanimura, Susumu [Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521 (Japan)] [Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521 (Japan); Koji, Takehiko [Department of Histology and Cell Biology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523 (Japan)] [Department of Histology and Cell Biology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523 (Japan); Kohno, Michiaki, E-mail: kohnom@nagasaki-u.ac.jp [Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521 (Japan) [Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521 (Japan); Proubase Technology Inc., Kanagawa 211-0063 (Japan); Kyoto University Graduate School of Pharmaceutical Sciences, Kyoto 606-8501 (Japan)

2013-04-19

316

Histone Deacetylase 1/Sp1/MicroRNA-200b Signaling Accounts for Maintenance of Cancer Stem-Like Cells in Human Lung Adenocarcinoma  

PubMed Central

The presence of cancer stem-like cells (CSCs) is one of the mechanisms responsible for chemoresistance that has been a major hindrance towards lung adenocarcinoma (LAD) treatment. Recently, we have identified microRNA (miR)-200b as a key regulator of chemoresistance in human docetaxel-resistant LAD cells. However, whether miR-200b has effects on regulating CSCs remains largely unclear and needs to be further elucidated. Here, we showed that miR-200b was significantly downregulated in CD133+/CD326+ cells that exhibited properties of CSCs derived from docetaxel-resistant LAD cells. Also, restoration of miR-200b could inhibit maintenance and reverse chemoresistance of CSCs. Furthermore, suppressor of zeste-12 (Suz-12) was identified as a direct and functional target of miR-200b, and silencing of Suz-12 phenocopied the effects of miR-200b on CSCs. Additionally, overexpression of histone deacetylase (HDAC) 1 was identified as a pivotal mechanism responsible for miR-200b repression in CSCs through a specificity protein (Sp) 1-dependent mechanism, and restoration of miR-200b by HDAC1 repression significantly suppressed CSCs formation and reversed chemoresistance of CSCs by regulating Suz-12-E-cadherin signaling. Also, downregulation of HDAC1 or upregulation of miR-200b reduced the in vivo tumorigenicity of CSCs. Finally, Suz-12 was inversely correlated with miR-200b, positively correlated with HDAC1 and up-regulated in docetaxel-resistant LAD tissues compared with docetaxel-sensitive tissues. Taken together, the HDAC1/miR-200b/Suz-12-E-cadherin signaling might account for maintenance of CSCs and formation of chemoresistant phenotype in docetaxel-resistant LAD cells. PMID:25279705

Pan, Ban-Zhou; De, Wei; Wang, Rui; Chen, Long-Bang

2014-01-01

317

HDAC4 degradation mediates HDAC inhibition-induced protective effects against hypoxia/reoxygenation injury.  

PubMed

Histone deacetylases (HDACs) play a crucial role in the regulation of gene expression through remodeling of chromatin structures. However, the molecular mechanisms involved in this event remain unknown. In this study, we sought to examine whether HDAC inhibition-mediated protective effects involved HDAC4 sumoylation, degradation, and the proteasome pathway. Isolated neonatal mouse ventricular myocytes (NMVM) and H9c2 cardiomyoblasts were subjected to 48?hours of hypoxia (H) (1% O2 ) and 2?hours of reoxygenation (R). Treatment of cardiomyocytes with trichostatin A (TSA) attenuated H/R-elicited injury, as indicated by a reduction of lactate dehydrogenase (LDH) leakage, an increase in cell viability, and decrease in apoptotic positive cardiomyocytes. MG132, a potent proteasome pathway inhibitor, abrogated TSA-induced protective effects, which was associated with the accumulation of ubiquitinated HDAC4. NMVM transduced with adenoviral HDAC4 led to an exaggeration of H/R-induced injury. TSA treatment resulted in a decrease in HDAC4 in cardiomyocytes infected with adenoviral HDAC4, and HDAC4-induced injury was attenuated by TSA. HDAC inhibition resulted in a significant reduction in reactive oxygen species (ROS) in cardiomyoblasts exposed to H/R, which was attenuated by blockade of the proteasome pathway. Cardiomyoblasts carrying wild type and sumoylation mutation (K559R) were established to examine effects of HDAC4 sumoylation and ubiquitination on H/R injury. Disruption of HDAC4 sumoylation brought about HDAC4 accumulation and impairment of HDAC4 ubiquitination in association with enhanced susceptibility of cardiomyoblasts to H/R. Taken together, these results demonstrated that HDAC inhibition stimulates proteasome dependent degradation of HDAC4, which is associated with HDAC4 sumoylation to induce these protective effects. This article is protected by copyright. All rights reserved. PMID:25475100

Du, Jianfeng; Zhang, Ling; Zhuang, Shougang; Qin, Gang J; Zhao, Ting

2014-12-01

318

Histone deacetylase 2 and N-Myc reduce p53 protein phosphorylation at serine 46 by repressing gene transcription of tumor protein 53-induced nuclear protein 1  

PubMed Central

Myc oncoproteins and histone deacetylases (HDACs) exert oncogenic effects by modulating gene transcription. Paradoxically, N-Myc induces p53 gene expression. Tumor protein 53-induced nuclear protein 1 (TP53INP1) phosphorylates p53 protein at serine 46, leading to enhanced p53 activity, transcriptional activation of p53 target genes and programmed cell death. Here we aimed to identify the mechanism through which N-Myc overexpressing p53 wild-type neuroblastoma cells acquired resistance to apoptosis. TP53INP1 was found to be one of the genes most significantly repressed by HDAC2 and N-Myc according to Affymetrix microarray gene expression datasets. HDAC2 and N-Myc reduced TP53INP1 gene expression by direct binding to the TP53INP1 gene promoter, leading to transcriptional repression of TP53INP1, p53 protein de-phosphorylation at serine 46, neuroblastoma cell proliferation and survival. Moreover, low levels of TP53INP1 expression in human neuroblastoma tissues correlated with high levels of N-Myc expression and poor patient outcome, and the BET bromodomain inhibitors JQ1 and I-BET151 reduced N-Myc expression and reactivated TP53INP1 expression in neuroblastoma cells. These findings identify TP53INP1 repression as an important co-factor for N-Myc oncogenesis, and provide further evidence for the potential application of BET bromodomain inhibitors in the therapy of N-Myc-induced neuroblastoma. PMID:24952595

Shahbazi, Jeyran; Scarlett, Christopher J.; Norris, Murray D.; Liu, Bing; Haber, Michelle; Tee, Andrew E.; Carrier, Alice; Biankin, Andrew V.; London, Wendy B.; Marshall, Glenn M.; Lock, Richard B.; Liu, Tao

2014-01-01

319

Histone deacetylase 2 and N-Myc reduce p53 protein phosphorylation at serine 46 by repressing gene transcription of tumor protein 53-induced nuclear protein 1.  

PubMed

Myc oncoproteins and histone deacetylases (HDACs) exert oncogenic effects by modulating gene transcription. Paradoxically, N-Myc induces p53 gene expression. Tumor protein 53-induced nuclear protein 1 (TP53INP1) phosphorylates p53 protein at serine 46, leading to enhanced p53 activity, transcriptional activation of p53 target genes and programmed cell death. Here we aimed to identify the mechanism through which N-Myc overexpressing p53 wild-type neuroblastoma cells acquired resistance to apoptosis. TP53INP1 was found to be one of the genes most significantly repressed by HDAC2 and N-Myc according to Affymetrix microarray gene expression datasets. HDAC2 and N-Myc reduced TP53INP1 gene expression by direct binding to the TP53INP1 gene promoter, leading to transcriptional repression of TP53INP1, p53 protein de-phosphorylation at serine 46, neuroblastoma cell proliferation and survival. Moreover, low levels of TP53INP1 expression in human neuroblastoma tissues correlated with high levels of N-Myc expression and poor patient outcome, and the BET bromodomain inhibitors JQ1 and I-BET151 reduced N-Myc expression and reactivated TP53INP1 expression in neuroblastoma cells. These findings identify TP53INP1 repression as an important co-factor for N-Myc oncogenesis, and provide further evidence for the potential application of BET bromodomain inhibitors in the therapy of N-Myc-induced neuroblastoma. PMID:24952595

Shahbazi, Jeyran; Scarlett, Christopher J; Norris, Murray D; Liu, Bing; Haber, Michelle; Tee, Andrew E; Carrier, Alice; Biankin, Andrew V; London, Wendy B; Marshall, Glenn M; Lock, Richard B; Liu, Tao

2014-06-30

320

Prenatal ethanol exposure causes glucose intolerance with increased hepatic gluconeogenesis and histone deacetylases in adult rat offspring: reversal by tauroursodeoxycholic acid.  

PubMed

Prenatal ethanol exposure results in increased glucose production in adult rat offspring and this may involve modulation of protein acetylation by cellular stress. We used adult male offspring of dams given ethanol during gestation days 1-7 (early), 8-14 (mid) and 15-21 (late) compared with those from control dams. A group of ethanol offspring was treated with tauroursodeoxycholic acid (TUDCA) for 3 weeks. We determined gluconeogenesis, phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase, hepatic free radicals, histone deacetylases (HDAC), acetylated foxo1, acetylated PEPCK, and C/EBP homologous protein as a marker of endoplasmic reticulum stress. Prenatal ethanol during either of the 3 weeks of pregnancy increased gluconeogenesis, gluconeogenic genes, oxidative and endoplasmic reticulum stresses, sirtuin-2 and HDAC3, 4, 5, and 7 in adult offspring. Conversely, prenatal ethanol reduced acetylation of foxo1 and PEPCK. Treatment of adult ethanol offspring with TUDCA reversed all these abnormalities. Thus, prenatal exposure of rats to ethanol results in long lasting oxidative and endoplasmic reticulum stresses explaining increased expression of gluconeogenic genes and HDAC proteins which, by deacetylating foxo1 and PEPCK, contribute to increased gluconeogenesis. These anomalies occurred regardless of the time of ethanol exposure during pregnancy, including early embryogenesis. As these anomalies were reversed by treatment of the adult offspring with TUDCA, this compound has therapeutic potentials in the treatment of glucose intolerance associated with prenatal ethanol exposure. PMID:23544086

Yao, Xing-Hai; Nguyen, Hoa K; Nyomba, B L Grégoire

2013-01-01

321

Trichostatin A, a histone deacetylase inhibitor, reverses epithelial-mesenchymal transition in colorectal cancer SW480 and prostate cancer PC3 cells.  

PubMed

Trichostatin A (TSA) is a kind of classical histone deacetylase (HDAC) inhibitor. In this study, we reported the reversal effects of TSA on EMT and investigated the possible involved molecular mechanisms in SW480 and PC3 cells. Firstly, we observed that TSA induced the reversal process of epithelial-mesenchymal transition (EMT) in SW480 and PC3 cells, resulting in attenuated cell invasion and migration abilities. TSA-induced EMT reversal was characterized by up-regulation of E-cadherin and down-regulation of Vimentin. Then, treatment with TSA also decreased the expression of transcription factor Slug. Furthermore, over-expression of Slug significantly caused down-regulation of E-cadherin and up-regulation of Vimentin. Meanwhile, TSA treatment in Slug-expressing cells could prevent these changes. These findings suggested that Slug played a crucial role in TSA-induced EMT reversal. Additionally, the study showed that TSA could induce the increase of HDAC1 and HDAC2 on the Slug gene promoter, which might be responsible for the suppression of Slug. Overall, TSA could reverse EMT in SW480 and PC3 cells and TSA-mediated down-regulation of Slug was involved in the reversal process. PMID:25434997

Wang, Xiaoxiong; Xu, Jun; Wang, Hao; Wu, Long; Yuan, Weiqi; Du, Jun; Cai, Shaohui

2015-01-01

322

Phase II study of the histone deacetylase inhibitor belinostat (PXD101) for the treatment of myelodysplastic syndrome (MDS).  

PubMed

The inhibition of histone deacetylase (HDAC) can induce differentiation, growth arrest, and apoptosis in cancer cells. This phase II multicenter study was undertaken to estimate the efficacy of belinostat, a potent inhibitor of both class I and class II HDAC enzymes, for the treatment of myelodysplastic syndrome (MDS). Adults with MDS and ?2 prior therapies were treated with belinostat 1,000 mg/m(2) IV on days 1-5 of a 21-day cycle. The primary endpoint was a proportion of confirmed responses during the first 12 weeks of treatment. Responding patients could receive additional cycles until disease progression or unacceptable toxicity. Twenty-one patients were enrolled, and all were evaluable. Patients were a median 13.4 months from diagnosis, and 14 patients (67%) had less than 5% bone marrow blasts. Seventeen patients (81%) were transfusion dependent. Prior therapy included azacytidine (n?=?7) and chemotherapy (n?=?8). The patients were treated with a median of four cycles (range, 1-8) of belinostat. There was one confirmed response-hematologic improvement in neutrophils-for an overall response rate of 5% (95% CI, 0.2-23). Median overall survival was 17.9 months. Grades 3-4 toxicities considered at least to be possibly related to belinostat were: neutropenia (n?=?10), thrombocytopenia (n?=?9), anemia (n?=?5), fatigue (n?=?2), febrile neutropenia (n?=?1), headache (n?=?1), and QTc prolongation (n?=?1). Because the study met the stopping rule in the first stage of enrollment, it was closed to further accrual. PMID:21538061

Cashen, Amanda; Juckett, Mark; Jumonville, Alcee; Litzow, Mark; Flynn, P J; Eckardt, John; LaPlant, Betsy; Laumann, Kristina; Erlichman, Charles; DiPersio, John

2012-01-01

323

Histone Deacetylase Inhibitor Upregulates Peroxisomal Fatty Acid Oxidation and Inhibits Apoptotic Cell Death in Abcd1-Deficient Glial Cells  

PubMed Central

In X-ALD, mutation/deletion of ALD gene (ABCD1) and the resultant very long chain fatty acid (VLCFA) derangement has dramatically opposing effects in astrocytes and oligodendrocytes. While loss of Abcd1 in astrocytes produces a robust inflammatory response, the oligodendrocytes undergo cell death leading to demyelination in X-linked adrenoleukodystrophy (X-ALD). The mechanisms of these distinct pathways in the two cell types are not well understood. Here, we investigated the effects of Abcd1-knockdown and the subsequent alteration in VLCFA metabolism in human U87 astrocytes and rat B12 oligodendrocytes. Loss of Abcd1 inhibited peroxisomal ?-oxidation activity and increased expression of VLCFA synthesizing enzymes, elongase of very long chain fatty acids (ELOVLs) (1 and 3) in both cell types. However, higher induction of ELOVL's in Abcd1-deficient B12 oligodendrocytes than astrocytes suggests that ELOVL pathway may play a prominent role in oligodendrocytes in X-ALD. While astrocytes are able to maintain the cellular homeostasis of anti-apoptotic proteins, Abcd1-deletion in B12 oligodendrocytes downregulated the anti-apototic (Bcl-2 and Bcl-xL) and cell survival (phospho-Erk1/2) proteins, and upregulated the pro-apoptotic proteins (Bad, Bim, Bax and Bid) leading to cell loss. These observations provide insights into different cellular signaling mechanisms in response to Abcd1-deletion in two different cell types of CNS. The apoptotic responses were accompanied by activation of caspase-3 and caspase-9 suggesting the involvement of mitochondrial-caspase-9-dependent mechanism in Abcd1-deficient oligodendrocytes. Treatment with histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) corrected the VLCFA derangement both in vitro and in vivo, and inhibited the oligodendrocytes loss. These observations provide a proof-of principle that HDAC inhibitor SAHA may have a therapeutic potential for X-ALD. PMID:23923017

Singh, Jaspreet; Khan, Mushfiquddin; Pujol, Aurora; Baarine, Mauhamad; Singh, Inderjit

2013-01-01

324

Research Article The histone deacetylase inhibitor trichostatin A influences  

E-print Network

of Drosophila melanogaster L.A. Pile, F. W.-H. Lee and D.A. Wassarman*, + National Institutes of Health trichostatin A (TSA) on the development of Drosophila melanogaster. When fed to flies, TSA caused lethality, and acted synergistically with mutations in the gene en- coding the RPD3 deacetylase to cause notched wings

Pile, Lori

325

Nanoparticles for urothelium penetration and delivery of the histone deacetylase inhibitor belinostat for treatment of bladder cancer  

PubMed Central

Nearly 40% of patients with non-invasive bladder cancer will progress to invasive disease despite locally-directed therapy. Overcoming the bladder permeability barrier (BPB) is a challenge for intravesical drug delivery. Using the fluorophore coumarin (C6), we synthesized C6-loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs), which were surface modified with a novel cell penetrating polymer, poly(guanidinium oxanorbornene) (PGON). Addition of PGON to the NP surface improved tissue penetration by 10-fold in intravesically-treated mouse bladder and ex vivo human ureter. In addition, NP-C6-PGON significantly enhanced intracellular uptake of NPs compared to NPs without PGON. To examine biological activity, we synthesized NPs that were loaded with the histone deacetylase (HDAC) inhibitor belinostat (NP-Bel-PGON). NP-Bel-PGON exhibited a significantly lower IC50 in cultured bladder cancer cells, and sustained hyperacetylation, when compared to unencapsulated belinostat. Xenograft tumors treated with NP-Bel-PGON showed a 70% reduction in volume, and a 2.5-fold higher intratumoral acetyl-H4, when compared to tumors treated with unloaded NP-PGON. PMID:23764660

Martin, Darryl T.; Hoimes, Christopher J.; Kaimakliotis, Hristos Z.; Cheng, Christopher J.; Zhang, Ke; Liu, Jingchun; Wheeler, Marcia A.; Kelly, W. Kevin; Tew, Greg N.; Saltzman, W. Mark; Weiss, Robert M.

2013-01-01

326

The histone deacetylase inhibitor LBH589 (panobinostat) modulates the crosstalk of lymphocytes with Hodgkin lymphoma cell lines.  

PubMed

Epigenetic changes have been implicated in the malignant phenotype of Hodgkin Reed Sternberg (HRS) cells in Hodgkin lymphoma (HL), where HRS survival and proliferation depends on the microenvironment. The histone-deacetylase (HDAC) inhibitor LBH589 (panobinostat) showed clinical efficacy but its impact on the HRS microenvironment is unclear. Hence, we analysed the effects of LBH589 on lymphocytes and also potential combination therapies. In lymphocyte-target cell killing assays, LBH589-treatment triggered an enhanced lymphocyte-dependent lysis of HL cells despite of mild lymphocytopenic effects. In co-culture experiments of lymphocytes with HL cells, LBH589 suppressed the IFNgamma-release but increased the TNFalpha secretion. Recombinant TNFalpha boosted the lymphocyte-dependent lysis of HL target cells. In HL cell lines, LBH589 induced cell death, autophagy, and an increase of MICA/B that are ligands to natural killer cell receptors. The combination of LBH589 with Brentuximab Vedotin was inefficient due to down-regulation of CD30 as a target. Combination with gemcitabine revealed highly significant effects, suggesting a potential combination for future therapy. Based on these data we suggest that LBH589 favourably modulates the cytokine network and lymphocyte activity in the HL microenvironment. PMID:24278143

Klein, Jan M; Henke, Alexander; Sauer, Maike; Bessler, Martina; Reiners, Katrin S; Engert, Andreas; Hansen, Hinrich P; von Strandmann, Elke Pogge

2013-01-01

327

The Histone Deacetylase Inhibitor LBH589 (Panobinostat) Modulates the Crosstalk of Lymphocytes with Hodgkin Lymphoma Cell Lines  

PubMed Central

Epigenetic changes have been implicated in the malignant phenotype of Hodgkin Reed Sternberg (HRS) cells in Hodgkin lymphoma (HL), where HRS survival and proliferation depends on the microenvironment. The histone-deacetylase (HDAC) inhibitor LBH589 (panobinostat) showed clinical efficacy but its impact on the HRS microenvironment is unclear. Hence, we analysed the effects of LBH589 on lymphocytes and also potential combination therapies. In lymphocyte-target cell killing assays, LBH589-treatment triggered an enhanced lymphocyte-dependent lysis of HL cells despite of mild lymphocytopenic effects. In co-culture experiments of lymphocytes with HL cells, LBH589 suppressed the IFNgamma-release but increased the TNFalpha secretion. Recombinant TNFalpha boosted the lymphocyte-dependent lysis of HL target cells. In HL cell lines, LBH589 induced cell death, autophagy, and an increase of MICA/B that are ligands to natural killer cell receptors. The combination of LBH589 with Brentuximab Vedotin was inefficient due to down-regulation of CD30 as a target. Combination with gemcitabine revealed highly significant effects, suggesting a potential combination for future therapy. Based on these data we suggest that LBH589 favourably modulates the cytokine network and lymphocyte activity in the HL microenvironment. PMID:24278143

Klein, Jan M.; Henke, Alexander; Sauer, Maike; Bessler, Martina; Reiners, Katrin S.; Engert, Andreas; Hansen, Hinrich P.; von Strandmann, Elke Pogge

2013-01-01

328

Histone Deacetylase Inhibition Decreases Cholesterol Levels in Neuronal Cells by Modulating Key Genes in Cholesterol Synthesis, Uptake and Efflux  

PubMed Central

Cholesterol is an essential component of the central nervous system and increasing evidence suggests an association between brain cholesterol metabolism dysfunction and the onset of neurodegenerative disorders. Interestingly, histone deacetylase inhibitors (HDACi) such as trichostatin A (TSA) are emerging as promising therapeutic approaches in neurodegenerative diseases, but their effect on brain cholesterol metabolism is poorly understood. We have previously demonstrated that HDACi up-regulate CYP46A1 gene transcription, a key enzyme in neuronal cholesterol homeostasis. In this study, TSA was shown to modulate the transcription of other genes involved in cholesterol metabolism in human neuroblastoma cells, namely by up-regulating genes that control cholesterol efflux and down-regulating genes involved in cholesterol synthesis and uptake, thus leading to an overall decrease in total cholesterol content. Furthermore, co-treatment with the amphipathic drug U18666A that can mimic the intracellular cholesterol accumulation observed in cells of Niemman-Pick type C patients, revealed that TSA can ameliorate the phenotype induced by pathological cholesterol accumulation, by restoring the expression of key genes involved in cholesterol synthesis, uptake and efflux and promoting lysosomal cholesterol redistribution. These results clarify the role of TSA in the modulation of neuronal cholesterol metabolism at the transcriptional level, and emphasize the idea of HDAC inhibition as a promising therapeutic tool in neurodegenerative disorders with impaired cholesterol metabolism. PMID:23326422

Nunes, Maria João; Moutinho, Miguel; Gama, Maria João; Rodrigues, Cecília M. P.; Rodrigues, Elsa

2013-01-01

329

Anticancer activity of SAHA, a potent histone deacetylase inhibitor, in NCI-H460 human large-cell lung carcinoma cells in vitro and in vivo.  

PubMed

Suberoylanilide hydroxamic acid (SAHA), a potent pan-histone deacetylase (HDAC) inhibitor, has been clinically approved for the treatment of cutaneous T-cell lymphoma (CTCL). SAHA has also been shown to exert a variety of anticancer activities in many other types of tumors, however, few studies have been reported in large-cell lung carcinoma (LCC). Our study aimed to investigate the potential antitumor effects of SAHA on LCC cells. Here, we report that SAHA was able to inhibit the proliferation of the LCC cell line NCI-H460 in a dose- and time-dependent manner, induced cell apoptosis and G2/M cell cycle arrest, decreased AKT and ERK phosphorylation, inhibited the expression of pro-angiogenic factors (VEGF, HIF-1?) in vitro, and suppressed tumor progression in an NCI-H460 cell nude mouse xenograft model in vivo. These results indicate that SAHA can exert its strong antitumor effects in LCC patient. PMID:24297449

Zhao, Yanxia; Yu, Dandan; Wu, Hongge; Liu, Hongli; Zhou, Hongxia; Gu, Runxia; Zhang, Ruiguang; Zhang, Sheng; Wu, Gang

2014-02-01

330

Effects of downregulated HDAC6 expression on the proliferation of lung cancer cells  

SciTech Connect

Histone deacetylase 6 (HDAC6) is a multifunctional, cytosolic protein deacetylase that primarily acts on {alpha}-tubulin. Here we report that stable knockdown of HDAC6 expression causes a decrease in the steady-state level of receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor {alpha}, in A549 lung cancer cells. The decreased levels of in EGFR in HDAC6-knockdown cells, which correlated with increased acetylation of microtubules, were due to increased turnover of EGFR protein. Despite the decrease in EGFR levels, A549 cells lacking functional HDAC6 appeared to grow normally, probably due to increased expression of extracellular signal-regulated kinases 1 and 2. Indeed, HDAC6-knockdown cells were more sensitive than control cells to the MEK inhibitor U0126. These results suggest that HDAC6 inhibitors combined with inhibitors of growth factor signaling may be useful as cancer therapy.

Kamemura, Kazuo [Chemical Genetics Laboratory, RIKEN Advanced Science Institute, Wako, Saitama 351-0198 (Japan); Japan Science and Technology Corporation, CREST Research Project, Kawaguchi, Saitama 332-0012 (Japan); Ito, Akihiro [Chemical Genetics Laboratory, RIKEN Advanced Science Institute, Wako, Saitama 351-0198 (Japan); Chemical Genomics Research Group, RIKEN Advanced Science Institute, Wako, Saitama 351-0198 (Japan)], E-mail: akihiro-i@riken.jp; Shimazu, Tadahiro [Chemical Genetics Laboratory, RIKEN Advanced Science Institute, Wako, Saitama 351-0198 (Japan); Matsuyama, Akihisa [Chemical Genetics Laboratory, RIKEN Advanced Science Institute, Wako, Saitama 351-0198 (Japan); Chemical Genomics Research Group, RIKEN Advanced Science Institute, Wako, Saitama 351-0198 (Japan); Japan Science and Technology Corporation, CREST Research Project, Kawaguchi, Saitama 332-0012 (Japan); Maeda, Satoko [Chemical Genetics Laboratory, RIKEN Advanced Science Institute, Wako, Saitama 351-0198 (Japan); Yao, Tso-Pang [Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710 (United States); Horinouchi, Sueharu [Department of Biotechnology, University of Tokyo, Tokyo 113-8657 (Japan); Khochbin, Saadi [INSERM U309, Institut Albert Bonniot, Faculte de Medecine, Domaine de la Merci, 38706 La Tronche Cedex (France); Yoshida, Minoru [Chemical Genetics Laboratory, RIKEN Advanced Science Institute, Wako, Saitama 351-0198 (Japan); Chemical Genomics Research Group, RIKEN Advanced Science Institute, Wako, Saitama 351-0198 (Japan); Japan Science and Technology Corporation, CREST Research Project, Kawaguchi, Saitama 332-0012 (Japan); Department of Biotechnology, University of Tokyo, Tokyo 113-8657 (Japan)

2008-09-12

331

Histone Deacetylases as Transcriptional Activators? Role Reversal in Inducible Gene Regulation  

NSDL National Science Digital Library

Posttranslational modifications regulate the activity, stability, and localization of proteins that can confer both positive and negative regulation to diverse biological systems. Acetylation is a protein modification that regulates eukaryotic gene expression. The addition of acetyl groups to nuclear proteins (such as histones and transcription factors) by histone acetyltransferase enzymes is frequently associated with activation of gene expression, whereas removal of acetyl groups by deacetylase enzymes is commonly associated with transcriptional repression. This article describes a number of exceptions to this general paradigm, indicating a previously unrecognized dynamic complexity in gene regulation by reversible acetylation.

Inna Nusinzon (Northwestern University and Evanston Northwestern Healthcare; Department of Medicine and Department of Biochemistry, Molecular Biology, and Cell Biology and Department of Medicine REV)

2005-08-09

332

Genome-wide binding map of the histone deacetylase Rpd3 in yeast  

Microsoft Academic Search

We describe the genome-wide distribution of the histone deacetylase and repressor Rpd3 and its associated proteins Ume1 and Ume6 in Saccharomyces cerevisiae. Using a new cross-linking protocol, we found that Rpd3 binds upstream of many individual genes and upstream of members of gene classes with similar functions in anabolic processes. In addition, Rpd3 is preferentially associated with promoters that direct

Siavash K. Kurdistani; Daniel Robyr; Saeed Tavazoie; Michael Grunstein

2002-01-01

333

A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer  

Microsoft Academic Search

Aberrant hypermethylation of gene promoters is a major mechanism associated with inactivation of tumor-suppressor genes in cancer. We previously showed this transcriptional silencing to be mediated by both methylation and histone deacetylase activity, with methylation being dominant. Here, we have used cDNA microarray analysis to screen for genes that are epigenetically silenced in human colorectal cancer. By screening over 10,000

Hiromu Suzuki; Edward Gabrielson; Wei Chen; Ramaswamy Anbazhagan; Manon van Engeland; Matty P. Weijenberg; James G. Herman; Stephen B. Baylin

2002-01-01

334

The Rpd3\\/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men  

Microsoft Academic Search

Protein lysine deacetylases have a pivotal role in numerous biological processes and can be divided into the Rpd3\\/Hda1 and sirtuin families, each having members in diverse organisms including prokaryotes. In vertebrates, the Rpd3\\/Hda1 family contains 11 members, traditionally referred to as histone deacetylases (HDAC) 1–11, which are further grouped into classes I, II and IV. Whereas most class I HDACs

Xiang-Jiao Yang; Edward Seto

2008-01-01

335

Search for the Pharmacophore of Histone Deacetylase Inhibitors Using Pharmacophore Query and Docking Study  

PubMed Central

Histone deacetylase inhibitors have gained a great deal of attention recently for the treatment of cancers and inflammatory diseases. So design of new inhibitors is of great importance in pharmaceutical industries and labs. Creating pharmacophor models in order to design new molecules or search a library for finding lead compounds is of great interest. This approach reduces the overall cost associated with the discovery and development of a new drug. Here we elaborated an exact pharmacophore model for histone deacetylase inhibitors by using pharmacophore query and docking study. The data set used for the modelling exercise comprised of 383 molecules collated from the original literature. These molecules were used to crating the model and docking study was held with Zolinza, the recently FDA approved drug as potent histone deacetylase inhibitor. Our model consists of 5 features: Hydrogen bond donors, Hydrogen bond acceptors, H-bond donor/acceptors, Aromatic ring centers, and hydrophobic centers. With the aid of this pharmacophore model and docking result, 3D searches in large databases can be performed, leading to a significant enrichment of active analogs.

Haji Agha Bozorgi, Atefeh; Zarghi, Afshin

2014-01-01

336

The effects of histone deacetylase inhibitors on glioblastoma-derived stem cells.  

PubMed

Glioblastoma multiforme (GBM) is the most malignant brain tumor with limited effective treatment options. Cancer stem cells (CSCs), a subpopulation of cancer cells with stem cell properties found in GBMs, have been shown to be extremely resistant to radiation and chemotherapeutic agents and have the ability to readily reform tumors. Therefore, the development of therapeutic agents targeting CSCs is extremely important. In this study, we isolated glioblastoma-derived stem cells (GDSCs) from GBM tissue removed from patients during surgery and analyzed their gene expression using quantitative real-time PCR and immunocytochemistry. We examined the effects of histone deacetylase inhibitors trichostatin A (TSA) and valproic acid (VPA) on the proliferation and gene expression profiles of GDSCs. The GDSCs expressed significantly higher levels of both neural and embryonic stem cell markers compared to GBM cells expanded in conventional monolayer cultures. Treatment of GDSCs with histone deacetylase inhibitors, TSA and VPA, significantly reduced proliferation rates of the cells and expression of the stem cell markers, indicating differentiation of the cells. Since differentiation into GBM makes them susceptible to the conventional cancer treatments, we posit that use of histone deacetylase inhibitors may increase efficacy of the conventional cancer treatments for eliminating GDSCs. PMID:24874578

Alvarez, Angel A; Field, Melvin; Bushnev, Sergey; Longo, Matthew S; Sugaya, Kiminobu

2015-01-01

337

HDAC6 deacetylates alpha tubulin in sperm and modulates sperm motility in Holtzman rat.  

PubMed

Histone deacetylase 6 (HDAC6) is an alpha (?)-tubulin deacetylase and its over-expression has been demonstrated to promote chemotactic cell movement. Motility in sperm is driven by the flagella, the cytoskeletal structure comprising the microtubules, which are heterodimers of ?- and ?-tubulins. We have hypothesized that HDAC6, by virtue of being an ?-tubulin deacetylase, might modulate sperm motility. However, the presence of HDAC6 on sperm has hitherto not been reported. In this study, we have demonstrated, for the first time, the presence of HDAC6 transcript and protein in the testicular and caudal sperm of rat. We have observed a significantly overlapping expression of HDAC6 with acetyl ?-tubulin (Ac ?-tubulin) in the mid-piece and principal piece of sperm flagella, and the co-precipitation of ?-tubulin and Ac ?-tubulin together with HDAC6 and vice versa in sperm lysates. This indicates that HDAC6 interacts with ?-tubulin. The HDAC6 activity of sperm, sperm motility and status of Ac ?-tubulin investigated in the presence of HDAC inhibitors Trichostatin A, Tubastatin A and sodium butyrate demonstrate that HDAC6 in sperm is catalytically active and that inhibitors of HDAC6 increase acetylation and restrict sperm motility. Thus, we show that (1) active HDAC6 enzyme is present in sperm, (2) HDAC6 in sperm is able to deacetylate ?-tubulin, (3) inhibition of HDAC6 results in increased Ac ?-tubulin expression and (4) HDAC6 inhibition affects sperm motility. This evidence suggests that HDAC6 is involved in modulating sperm movement. PMID:25411052

Parab, Sweta; Shetty, Omshree; Gaonkar, Reshma; Balasinor, Nafisa; Khole, Vrinda; Parte, Priyanka

2014-11-20

338

First-in-human, Pharmacokinetic and Pharmacodynamic Phase I Study of Resminostat, an Oral Histone Deacetylase Inhibitor, in Patients with Advanced Solid Tumors  

PubMed Central

Purpose This first-in-human dose-escalating trial investigated the safety, tolerability, maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics and pharmacodynamics of the novel histone deacetylase (HDAC) inhibitor resminostat in patients with advanced solid tumors. Experimental Design Resminostat was administered orally once-daily on days 1-5 every 14 days at 5 dose levels between 100 mg and 800 mg. Safety, pharmacokinetics, pharmacodynamics including histone acetylation and HDAC enzyme activity, and antitumor efficacy were assessed. Results Nineteen patients (median age 58 years, range 39-70) were treated. At 800 mg, 1 patient experienced grade 3 nausea and vomiting, grade 2 liver enzyme elevation, and grade 1 hypokalemia and thrombocytopenia; these were declared as a combined DLT. No other DLT was observed. Although an MTD was not reached and patients were safely dosed up to 800 mg, 3 of 7 patients treated with 800 mg underwent dose reductions after the DLT-defining period due to cumulative gastrointestinal toxicities and fatigue. All toxicities resolved following drug cessation. No grade 4 treatment-related adverse event was observed. The pharmacokinetic profile was dose-proportional with low inter-patient variability. Pharmacodynamic inhibition of HDAC enzyme was dose-dependent and reached 100% at doses ?400 mg. Eleven heavily pre-treated patients had stable disease and 1 patient with metastatic thymoma had a 27% reduction in target lesion dimensions. Conclusions Resminostat was safely administered with a dose-proportional pharmacokinetic profile, optimal on-target pharmacodynamic activity at dose levels ?400 mg and signs of antitumor efficacy. The recommended phase II dose is 600 mg once-daily on days 1-5 every 14 days. PMID:24065624

Brunetto, André T.; Ang, Joo Ern; Lal, Rohit; Olmos, David; Molife, L. Rhoda; Kristeleit, Rebecca; Parker, Ann; Casamayor, Isabel; Olaleye, Muyibat; Mais, Anna; Hauns, Bernhard; Strobel, Vera; Hentsch, Bernd; de Bono, Johann S.

2013-01-01

339

Displacement of SATB1-bound histone deacetylase 1 corepressor by the human immunodeficiency virus type 1 transactivator induces expression of interleukin-2 and its receptor in T cells.  

PubMed

One hallmark of human immunodeficiency virus type 1 (HIV-1) infection is the dysregulation of cytokine gene expression in T cells. Transfection of T cells with human T-cell leukemia type 1 or 2 transactivator results in the induction of the T-cell-restricted cytokine interleukin-2 (IL-2) and its receptor (IL-2Ralpha). However, no T-cell-specific factor(s) has been directly linked with the regulation of IL-2 and IL-2Ralpha transcription by influencing the promoter activity. Thymocytes from SATB1 (special AT-rich sequence binding protein 1) knockout mice have been shown to ectopically express IL-2Ralpha, suggesting involvement of SATB1 in its negative regulation. Here we show that SATB1, a T-cell-specific global gene regulator, binds to the promoters of human IL-2 and IL-2Ralpha and recruits histone deacetylase 1 (HDAC1) in vivo. SATB1 also interacts with Tat in HIV-1-infected T cells. The functional interaction between HIV-1 Tat and SATB1 requires its PDZ-like domain, and the binding of the HDAC1 corepressor occurs through the same. Furthermore, Tat competitively displaces HDAC1 that is bound to SATB1, leading to increased acetylation of the promoters in vivo. Transduction with SATB1 interaction-deficient soluble Tat (Tat 40-72) and reporter assays using a transactivation-negative mutant (C22G) of Tat unequivocally demonstrated that the displacement of HDAC1 itself is sufficient for derepression of these promoters in vivo. These results suggest a novel mechanism by which HIV-1 Tat might overcome SATB1-mediated repression in T cells. PMID:15713622

Kumar, P Pavan; Purbey, Prabhat Kumar; Ravi, Dyavar S; Mitra, Debashis; Galande, Sanjeev

2005-03-01

340

Displacement of SATB1-Bound Histone Deacetylase 1 Corepressor by the Human Immunodeficiency Virus Type 1 Transactivator Induces Expression of Interleukin-2 and Its Receptor in T Cells  

PubMed Central

One hallmark of human immunodeficiency virus type 1 (HIV-1) infection is the dysregulation of cytokine gene expression in T cells. Transfection of T cells with human T-cell leukemia type 1 or 2 transactivator results in the induction of the T-cell-restricted cytokine interleukin-2 (IL-2) and its receptor (IL-2R?). However, no T-cell-specific factor(s) has been directly linked with the regulation of IL-2 and IL-2R? transcription by influencing the promoter activity. Thymocytes from SATB1 (special AT-rich sequence binding protein 1) knockout mice have been shown to ectopically express IL-2R?, suggesting involvement of SATB1 in its negative regulation. Here we show that SATB1, a T-cell-specific global gene regulator, binds to the promoters of human IL-2 and IL-2R? and recruits histone deacetylase 1 (HDAC1) in vivo. SATB1 also interacts with Tat in HIV-1-infected T cells. The functional interaction between HIV-1 Tat and SATB1 requires its PDZ-like domain, and the binding of the HDAC1 corepressor occurs through the same. Furthermore, Tat competitively displaces HDAC1 that is bound to SATB1, leading to increased acetylation of the promoters in vivo. Transduction with SATB1 interaction-deficient soluble Tat (Tat 40-72) and reporter assays using a transactivation-negative mutant (C22G) of Tat unequivocally demonstrated that the displacement of HDAC1 itself is sufficient for derepression of these promoters in vivo. These results suggest a novel mechanism by which HIV-1 Tat might overcome SATB1-mediated repression in T cells. PMID:15713622

Kumar, P. Pavan; Purbey, Prabhat Kumar; Ravi, Dyavar S.; Mitra, Debashis; Galande, Sanjeev

2005-01-01

341

Computational Exploration of Zinc Binding Groups for HDAC Inhibition  

PubMed Central

Histone deacetylases (HDACs) emerged as important drug targets in epigenetics. The most common HDAC inhibitors use hydroxamic acids as zinc binding groups despite unfavorable pharmacokinetic properties. A two-stage protocol of M05-2X calculations of a library of 48 fragments in a small model active site, followed by QM/MM hybrid calculations of the full enzyme with selected binders is used to prospectively select potential bidentate zinc binders. The energetics and interaction patterns of several zinc binders not previously used for the inhibition of HDACs are discussed. PMID:23586590

Chen, Kai; Xu, Liping

2013-01-01

342

Class IIb HDAC6 regulates endothelial cell migration and angiogenesis by deacetylation of cortactin.  

PubMed

Histone deacetylases (HDACs) deacetylate histones and non-histone proteins, thereby affecting protein activity and gene expression. The regulation and function of the cytoplasmic class IIb HDAC6 in endothelial cells (ECs) is largely unexplored. Here, we demonstrate that HDAC6 is upregulated by hypoxia and is essential for angiogenesis. Silencing of HDAC6 in ECs decreases sprouting and migration in vitro and formation of functional vascular networks in matrigel plugs in vivo. HDAC6 regulates zebrafish vessel formation, and HDAC6-deficient mice showed a reduced formation of perfused vessels in matrigel plugs. Consistently, overexpression of wild-type HDAC6 increases sprouting from spheroids. HDAC6 function requires the catalytic activity but is independent of ubiquitin binding and deacetylation of ?-tubulin. Instead, we found that HDAC6 interacts with and deacetylates the actin-remodelling protein cortactin in ECs, which is essential for zebrafish vessel formation and which mediates the angiogenic effect of HDAC6. In summary, we show that HDAC6 is necessary for angiogenesis in vivo and in vitro, involving the interaction and deacetylation of cortactin that regulates EC migration and sprouting. PMID:21847094

Kaluza, David; Kroll, Jens; Gesierich, Sabine; Yao, Tso-Pang; Boon, Reinier A; Hergenreider, Eduard; Tjwa, Marc; Rössig, Lothar; Seto, Edward; Augustin, Hellmut G; Zeiher, Andreas M; Dimmeler, Stefanie; Urbich, Carmen

2011-10-19

343

Class IIb HDAC6 regulates endothelial cell migration and angiogenesis by deacetylation of cortactin  

PubMed Central

Histone deacetylases (HDACs) deacetylate histones and non-histone proteins, thereby affecting protein activity and gene expression. The regulation and function of the cytoplasmic class IIb HDAC6 in endothelial cells (ECs) is largely unexplored. Here, we demonstrate that HDAC6 is upregulated by hypoxia and is essential for angiogenesis. Silencing of HDAC6 in ECs decreases sprouting and migration in vitro and formation of functional vascular networks in matrigel plugs in vivo. HDAC6 regulates zebrafish vessel formation, and HDAC6-deficient mice showed a reduced formation of perfused vessels in matrigel plugs. Consistently, overexpression of wild-type HDAC6 increases sprouting from spheroids. HDAC6 function requires the catalytic activity but is independent of ubiquitin binding and deacetylation of ?-tubulin. Instead, we found that HDAC6 interacts with and deacetylates the actin-remodelling protein cortactin in ECs, which is essential for zebrafish vessel formation and which mediates the angiogenic effect of HDAC6. In summary, we show that HDAC6 is necessary for angiogenesis in vivo and in vitro, involving the interaction and deacetylation of cortactin that regulates EC migration and sprouting. PMID:21847094

Kaluza, David; Kroll, Jens; Gesierich, Sabine; Yao, Tso-Pang; Boon, Reinier A; Hergenreider, Eduard; Tjwa, Marc; Rössig, Lothar; Seto, Edward; Augustin, Hellmut G; Zeiher, Andreas M; Dimmeler, Stefanie; Urbich, Carmen

2011-01-01

344

Histone deacetylase 6-mediated deacetylation of ?-tubulin coordinates cytoskeletal and signaling events during platelet activation  

PubMed Central

The tubulin cytoskeleton plays a key role in maintaining the characteristic quiescent discoid shape of resting platelets. Upon activation, platelets undergo a dramatic change in shape; however, little is known of how the microtubule system contributes to regulating platelet shape and function. Here we investigated the role of the covalent modification of ?-tubulin by acetylation in the regulation of platelet physiology during activation. Superresolution microscopy analysis of the platelet tubulin cytoskeleton showed that the marginal band together with an interconnected web of finer tubulin structures collapsed upon platelet activation with the glycoprotein VI (GPVI)-agonist collagen-related peptide (CRP). Western blot analysis revealed that ?-tubulin was acetylated in resting platelets and deacetylated during platelet activation. Tubacin, a specific inhibitor of the tubulin deacetylase HDAC6, prevented tubulin deacetylation upon platelet activation with CRP. Inhibition of HDAC6 upregulated tubulin acetylation and disrupted the organization of the platelet microtubule marginal band without significantly affecting platelet volume changes in response to CRP stimulation. HDAC6 inhibitors also inhibited platelet aggregation in response to CRP and blocked platelet signaling events upstream of platelet Rho GTPase activation. Together, these findings support a role for acetylation signaling in controlling the resting structure of the platelet tubulin marginal band as well as in the coordination of signaling systems that drive platelet cytoskeletal changes and aggregation. PMID:24025866

Phillips, Kevin G.; Healy, Laura D.; Itakura, Asako; Pang, Jiaqing; McCarty, Owen J. T.

2013-01-01

345

A novel small molecule hybrid of vorinostat and DACA displays anticancer activity against human hormone-refractory metastatic prostate cancer through dual inhibition of histone deacetylase and topoisomerase I.  

PubMed

Vorinostat, which is an extensively studied inhibitor against histone deacetylase (HDAC), shows limited clinical activity to solid tumors. WJ35435, a new hybrid of vorinostat and DACA (a topoisomerase inhibitor) potently inhibited HDAC activity (in particular HDAC1 and HDAC6) in kinase assay and cell-based examination. The anti-HDAC effect was confirmed by the induction of histone H3 acetylation and phosphorylation, ?-tubulin acetylation and ?-H2AX formation. WJ35435 showed better potency than vorinostat and DACA against PC-3 and DU-145, two human hormone-refractory metastatic prostate cancer (HRMPC) cell lines, but not benign prostate cells. WJ35435 at differential concentrations induced G1- or G2-phase arrest of the cell cycle in HRMPCs but not in benign prostate cells. WJ35435 induced the formation of topoisomerase I-DNA cleavable complexes but not type-II? or -II?. Topoisomerase activity assay confirmed the selective inhibition of topoisomerase I. WJ35435 induced profound DNA damage using comet tailing assay. WJ35435 was less effective than camptothecin and etoposide in inducing the phosphorylation and activation of Chk1, Chk2 and RPA32 which were crucial coordinators in DNA repair pathway, indicating a low DNA repair activity to WJ35435 action. Furthermore, WJ35435 showed an in vivo antitumor activity. A synergistic apoptosis (combination index=0.55) was obtained in combination between WJ35435 and MG-132 (a proteasome inhibitor). In summary, WJ35435 is a dual-targeted anticancer hybrid induces anti-HDAC and anti-topoisomerase I activities that cause DNA damage associated with a low DNA repair capability, and induce cell cycle arrest at G1- and G2-phase. Ultimately, WJ35435 inhibits cell proliferation and induces apoptosis of HRMPCs. PMID:24915421

Yu, Chia-Chun; Pan, Shiow-Lin; Chao, Shi-Wei; Liu, Shih-Ping; Hsu, Jui-Ling; Yang, Yu-Chen; Li, Tsia-Kun; Huang, Wei-Jan; Guh, Jih-Hwa

2014-08-01

346

Short-Chain HDAC Inhibitors Differentially Affect Vertebrate Development and Neuronal Chromatin  

PubMed Central

Carboxylic acids with known central nervous system and histone deacetylase (HDAC) inhibitory activities were converted to hydroxamic acids and tested using a suite of in vitro biochemical assays with recombinant HDAC isoforms, cell based assays in human cervical carcinoma HeLa cells and primary cultures from mouse forebrain, and a whole animal (Xenopus laevis) developmental assay. Relative to the parent carboxylic acids, two of these analogues exhibited enhanced potency, and one analogue showed altered HDAC isoform selectivity and in vivo activity in the Xenopus assay. We discuss potential uses of these novel hydroxamic acids in studies aimed at determining the utility of HDAC inhibitors as memory enhancers and mood stabilizers. PMID:21874153

2010-01-01

347

Significant Improvement in Cloning Efficiency of an Inbred Miniature Pig by Histone Deacetylase Inhibitor Treatment after Somatic Cell Nuclear Transfer1  

PubMed Central

The National Institutes of Health (NIH) miniature pig was developed specifically for xenotransplantation and has been extensively used as a large-animal model in many other biomedical experiments. However, the cloning efficiency of this pig is very low (<0.2%), and this has been an obstacle to the promising application of these inbred swine genetics for biomedical research. It has been demonstrated that increased histone acetylation in somatic cell nuclear transfer (SCNT) embryos, by applying a histone deacetylase (HDAC) inhibitor such as trichostatin A (TSA), significantly enhances the developmental competence in several species. However, some researchers also reported that TSA treatment had various detrimental effects on the in vitro and in vivo development of the SCNT embryos. Herein, we report that treatment with 500 nM 6-(1,3-dioxo-1H, 3H-benzo[de]isoquinolin-2-yl)-hexanoic acid hydroxyamide (termed scriptaid), a novel HDAC inhibitor, significantly enhanced the development of SCNT embryos to the blastocyst stage when NIH inbred fetal fibroblast cells (FFCs) were used as donors compared with the untreated group (21% vs. 9%, P < 0.05). Scriptaid treatment resulted in eight pregnancies from 10 embryo transfers (ETs) and 14 healthy NIH miniature pigs from eight litters, while no viable piglets (only three mummies) were obtained from nine ETs in the untreated group. Thus, scriptaid dramatically increased the cloning efficiency when using inbred genetics from 0.0% to 1.3%. In contrast, scriptaid treatment decreased the blastocyst rate in in vitro fertilization embryos (from 37% to 26%, P < 0.05). In conclusion, the extremely low cloning efficiency in the NIH miniature pig may be caused by its inbred genetic background and can be improved by alteration of genomic histone acetylation patterns. PMID:19386991

Zhao, Jianguo; Ross, Jason W.; Hao, Yanhong; Spate, Lee D.; Walters, Eric M.; Samuel, Melissa S.; Rieke, August; Murphy, Clifton N.; Prather, Randall S.

2009-01-01

348

Histone H3 lysine 36 methylation antagonizes silencing in Saccharomyces cerevisiae independently of the Rpd3S histone deacetylase complex.  

PubMed

In yeast, methylation of histone H3 on lysine 36 (H3-K36) is catalyzed by the NSD1 leukemia oncoprotein homolog Set2. The histone deacetylase complex Rpd3S is recruited to chromatin via binding of the chromodomain protein Eaf3 to methylated H3-K36 to prevent erroneous transcription initiation. Here we identify a distinct function for H3-K36 methylation. We used random mutagenesis of histones H3 and H4 followed by a reporter-based screen to identify residues necessary to prevent the ectopic spread of silencing from the silent mating-type locus HMRa into flanking euchromatin. Mutations in H3-K36 or deletion of SET2 caused ectopic silencing of a heterochromatin-adjacent reporter. Transcriptional profiling revealed that telomere-proximal genes are enriched for those that display decreased expression in a set2Delta strain. Deletion of SIR4 rescued the expression defect of 26 of 37 telomere-proximal genes with reduced expression in set2Delta cells, implying that H3-K36 methylation prevents the spread of telomeric silencing. Indeed, Sir3 spreads from heterochromatin into neighboring euchromatin in set2Delta cells. Furthermore, genetic experiments demonstrated that cells lacking the Rpd3S-specific subunits Eaf3 or Rco1 did not display the anti-silencing phenotype of mutations in SET2 or H3-K36. Thus, antagonism of silencing is independent of the only known effector of this conserved histone modification. PMID:17179083

Tompa, Rachel; Madhani, Hiten D

2007-02-01

349

Genome-Wide Histone Acetylation Profiling of Herpesvirus saimiri in Human T Cells upon Induction with a Histone Deacetylase Inhibitor?†  

PubMed Central

Herpesviruses establish latency in suitable host cells after primary infection and persist in their host organisms for life. Most of the viral genes are silenced during latency, also enabling the virus to escape from an immune response. This study addresses the control of viral gene silencing by epigenetic mechanisms, using Herpesvirus saimiri (HVS) as a model system. Strain C488 of this gamma-2-herpesvirus can transform human T cells to stable growth in vitro, and it persists in the nuclei of those latently infected T cells as a nonintegrating, circular, and histone-associated episome. The whole viral genome was probed for histone acetylation at high resolution by chromatin immunoprecipitation-on-chip (ChIP-on-chip) with a custom tiling microarray. Corresponding to their inactive status in human T cells, the lytic promoters consistently revealed a heterochromatic phenotype. In contrast, the left terminal region of the genome, which encodes the stably expressed oncogenes stpC and tip as well as the herpesvirus U RNAs, was associated with euchromatic histone acetylation marks representing “open” chromatin. Although HVS latency in human T lymphocytes is considered a stable and irreversible state, incubation with the histone deacetylase inhibitor trichostatin A resulted in changes reminiscent of the induction of early lytic replication. However, infectious viral particles were not produced, as the majority of cells went into apoptosis. These data show that epigenetic mechanisms are involved in both rhadinoviral latency and transition into lytic replication. PMID:21430050

Alberter, Barbara; Vogel, Benjamin; Lengenfelder, Doris; Full, Florian; Ensser, Armin

2011-01-01

350

Genome-wide histone acetylation profiling of Herpesvirus saimiri in human T cells upon induction with a histone deacetylase inhibitor.  

PubMed

Herpesviruses establish latency in suitable host cells after primary infection and persist in their host organisms for life. Most of the viral genes are silenced during latency, also enabling the virus to escape from an immune response. This study addresses the control of viral gene silencing by epigenetic mechanisms, using Herpesvirus saimiri (HVS) as a model system. Strain C488 of this gamma-2-herpesvirus can transform human T cells to stable growth in vitro, and it persists in the nuclei of those latently infected T cells as a nonintegrating, circular, and histone-associated episome. The whole viral genome was probed for histone acetylation at high resolution by chromatin immunoprecipitation-on-chip (ChIP-on-chip) with a custom tiling microarray. Corresponding to their inactive status in human T cells, the lytic promoters consistently revealed a heterochromatic phenotype. In contrast, the left terminal region of the genome, which encodes the stably expressed oncogenes stpC and tip as well as the herpesvirus U RNAs, was associated with euchromatic histone acetylation marks representing "open" chromatin. Although HVS latency in human T lymphocytes is considered a stable and irreversible state, incubation with the histone deacetylase inhibitor trichostatin A resulted in changes reminiscent of the induction of early lytic replication. However, infectious viral particles were not produced, as the majority of cells went into apoptosis. These data show that epigenetic mechanisms are involved in both rhadinoviral latency and transition into lytic replication. PMID:21430050

Alberter, Barbara; Vogel, Benjamin; Lengenfelder, Doris; Full, Florian; Ensser, Armin

2011-06-01

351

Cardiac HDAC6 catalytic activity is induced in response to chronic hypertension.  

PubMed

Small molecule histone deacetylase (HDAC) inhibitors block adverse cardiac remodeling in animal models of heart failure. The efficacious compounds target class I, class IIb and, to a lesser extent, class IIa HDACs. It is hypothesized that a selective inhibitor of a specific HDAC class (or an isoform within that class) will provide a favorable therapeutic window for the treatment of heart failure, although the optimal selectivity profile for such a compound remains unknown. Genetic studies have suggested that class I HDACs promote pathological cardiac remodeling, while class IIa HDACs are protective. In contrast, nothing is known about the function or regulation of class IIb HDACs in the heart. We developed assays to quantify catalytic activity of distinct HDAC classes in left and right ventricular cardiac tissue from animal models of hypertensive heart disease. Class I and IIa HDAC activity was elevated in some but not all diseased tissues. In contrast, catalytic activity of the class IIb HDAC, HDAC6, was consistently increased in stressed myocardium, but not in a model of physiologic hypertrophy. HDAC6 catalytic activity was also induced by diverse extracellular stimuli in cultured cardiac myocytes and fibroblasts. These findings suggest an unforeseen role for HDAC6 in the heart, and highlight the need for pre-clinical evaluation of HDAC6-selective inhibitors to determine whether this HDAC isoform is pathological or protective in the setting of cardiovascular disease. PMID:21539845

Lemon, Douglas D; Horn, Todd R; Cavasin, Maria A; Jeong, Mark Y; Haubold, Kurt W; Long, Carlin S; Irwin, David C; McCune, Sylvia A; Chung, Eunhee; Leinwand, Leslie A; McKinsey, Timothy A

2011-07-01

352

Inhibition of Histone Deacetylases Induces Bovine Leukemia Virus Expression In Vitro and In Vivo  

PubMed Central

Packaging into nucleosomes results in a global transcriptional repression as a consequence of exclusion of sequence-specific factors. This inhibition can be relieved by using inhibitors of histone deacetylases, acetylation being a major characteristic of transcriptionally active chromatin. Paradoxically, the expression of only ?2% of the total cellular genes is modulated by histone hyperacetylation. To unravel the potential role of this transcriptional control on BLV expression, we tested the effect of two highly specific inhibitors of deacetylases, trichostatin A (TSA) and trapoxin (TPX). Our results demonstrate that treatment with TSA efficiently enhanced long terminal repeat-directed gene expression of integrated reporter constructs in heterologous D17 stable cell lines. To further examine the biological relevance of these observations made in vitro, we analyzed ex vivo-isolated peripheral blood mononuclear cells (PBMCs) from bovine leukemia virus (BLV)-infected sheep. TSA deacetylase inhibitor induced a drastic increase in viral expression at levels comparable to those induced by treatment with phorbol-12-myristate 13-acetate and ionomycin, the most efficient activators of BLV expression known to date. TSA acted directly on BLV-infected B lymphocytes to increase viral expression and does not seem to require T-cell cooperation. Inhibition of deacetylation after treatment with TSA or TPX also significantly increased viral expression in PBMCs from cattle, the natural host for BLV. Together, our results show that BLV gene expression is, like that of a very small fraction of cellular genes, also regulated by deacetylation. PMID:11967319

Merezak, C.; Reichert, M.; Van Lint, C.; Kerkhofs, P.; Portetelle, D.; Willems, L.; Kettmann, R.

2002-01-01

353

Histone deacetylase 4 promotes ubiquitin-dependent proteasomal degradation of Sp3 in SH-SY5Y cells treated with di(2-ethylhexyl)phthalate (DEHP), determining neuronal death.  

PubMed

Phthalates, phthalic acid esters, are widely used as plasticizers to produce polymeric materials in industrial production of plastics and daily consumable products. Animal studies have shown that di(2-ethylhexyl)phthalate (DEHP) may cause toxic effects in the rat brain. In the present study, chronic exposure to DEHP (0.1-100?M) caused dose-dependent cell death via the activation of caspase-3 in neuroblastoma cells. Intriguingly, this harmful effect was prevented by the pan-histone deacetylase (HDAC) inhibitor trichostatin A, by the class II HDAC inhibitor MC-1568, but not by the class I HDAC inhibitor MS-275. Furthermore, DEHP reduced specificity protein 3 (Sp3) gene expression, but not Sp3 mRNA, after 24 and 48h exposures. However, Sp3 protein reduction was prevented by pre-treatment with MC-1568, suggesting the involvement of class II HDACs in causing this effect. Then, we investigated the possible relationship between DEHP-induced neuronal death and the post-translational mechanisms responsible for the down-regulation of Sp3. Interestingly, DEHP-induced Sp3 reduction was associated to its deacetylation and polyubiquitination. Co-immunoprecipitation studies showed that Sp3 physically interacted with HDAC4 after DEHP exposure, while HDAC4 inhibition by antisense oligodeoxynucleotide reverted the DEHP-induced degradation of Sp3. Notably, Sp3 overexpression was able to counteract the detrimental effect induced by DEHP. Taken together, these results suggest that DEHP exerts its toxic effect by inducing deacetylation of Sp3 via HDAC4, and afterwards, Sp3-polyubiquitination. PMID:25068794

Guida, Natascia; Laudati, Giusy; Galgani, Mario; Santopaolo, Marianna; Montuori, Paolo; Triassi, Maria; Di Renzo, Gianfranco; Canzoniero, Lorella M T; Formisano, Luigi

2014-10-01