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1

Histone deacetylases (HDACs): characterization of the classical HDAC family.  

PubMed Central

Transcriptional regulation in eukaryotes occurs within a chromatin setting, and is strongly influenced by the post-translational modification of histones, the building blocks of chromatin, such as methylation, phosphorylation and acetylation. Acetylation is probably the best understood of these modifications: hyperacetylation leads to an increase in the expression of particular genes, and hypoacetylation has the opposite effect. Many studies have identified several large, multisubunit enzyme complexes that are responsible for the targeted deacetylation of histones. The aim of this review is to give a comprehensive overview of the structure, function and tissue distribution of members of the classical histone deacetylase (HDAC) family, in order to gain insight into the regulation of gene expression through HDAC activity. SAGE (serial analysis of gene expression) data show that HDACs are generally expressed in almost all tissues investigated. Surprisingly, no major differences were observed between the expression pattern in normal and malignant tissues. However, significant variation in HDAC expression was observed within tissue types. HDAC inhibitors have been shown to induce specific changes in gene expression and to influence a variety of other processes, including growth arrest, differentiation, cytotoxicity and induction of apoptosis. This challenging field has generated many fascinating results which will ultimately lead to a better understanding of the mechanism of gene transcription as a whole. PMID:12429021

de Ruijter, Annemieke J M; van Gennip, Albert H; Caron, Huib N; Kemp, Stephan; van Kuilenburg, André B P

2003-01-01

2

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

3

Histone deacetylases (HDACs) in XPC gene silencing and bladder cancer  

PubMed Central

Bladder cancer is one of the most common malignancies and causes hundreds of thousands of deaths worldwide each year. Bladder cancer is strongly associated with exposure to environmental carcinogens. It is believed that DNA damage generated by environmental carcinogens and their metabolites causes development of bladder cancer. Nucleotide excision repair (NER) is the major DNA repair pathway for repairing bulk DNA damage generated by most environmental carcinogens, and XPC is a DNA damage recognition protein required for initiation of the NER process. Recent studies demonstrate reduced levels of XPC protein in tumors for a majority of bladder cancer patients. In this work we investigated the role of histone deacetylases (HDACs) in XPC gene silencing and bladder cancer development. The results of our HDAC inhibition study revealed that the treatment of HTB4 and HTB9 bladder cancer cells with the HDAC inhibitor valproic acid (VPA) caused an increase in transcription of the XPC gene in these cells. The results of our chromatin immunoprecipitation (ChIP) studies indicated that the VPA treatment caused increased binding of both CREB1 and Sp1 transcription factors at the promoter region of the XPC gene for both HTB4 and HTB9 cells. The results of our immunohistochemistry (IHC) staining studies further revealed a strong correlation between the over-expression of HDAC4 and increased bladder cancer occurrence (p < 0.001) as well as a marginal significance of increasing incidence of HDAC4 positivity seen with an increase in severity of bladder cancer (p = 0.08). In addition, the results of our caspase 3 activation studies demonstrated that prior treatment with VPA increased the anticancer drug cisplatin-induced activation of caspase 3 in both HTB4 and HTB9 cells. All of these results suggest that the HDACs negatively regulate transcription of the XPC gene in bladder cancer cells and contribute to the severity of bladder tumors. PMID:21507255

2011-01-01

4

Histone Deacetylase Inhibitors: Mechanisms and Clinical Significance in Cancer: HDAC Inhibitor-Induced Apoptosis  

Microsoft Academic Search

Epigenic modifications, mainly DNA methylation and acetylation, are recognized as the main mechanisms contributing to the\\u000a malignant phenotype. Acetylation and deacetylation are catalyzed by specific enzymes, histone acetyltransferases (HATs) and\\u000a histone deacetylases (HDACs), respectively. While histones represent a primary target for the physiological function of HDACs,\\u000a the antitumor effect of HDAC inhibitors might also be attributed to transcriptionindependent mechanisms by

Sharmila Shankar; Rakesh K. Srivastava

5

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

6

Histone Deacetylase 4 (HDAC4): Mechanism of Regulations and Biological Functions  

PubMed Central

The acetylation and deacetylation of histones play an important role in the regulation of gene transcriptions. Histone acetylation is mediated by histone acetyltransferase (HAT). The resulting modification in the structure of chromatin leads to nucleosomal relaxation and altered transcriptional activation. The reverse reaction is mediated by histone deacetylase (HDAC), which induces deacetylation, chromatin condensation, and transcriptional repression. HDACs are divided into three distinct classes, I, II, and III, on the basis of size, sequence homology, as well as formation of distinct complexes. Among class II HDACs, HDAC4 is implicated in controlling gene expression important for diverse cellular functions. Basic and clinical experimental evidence have well established that HDAC4 performs a wide variety of functions. Understanding the biological significance of HDAC4 will not only provide new insight into the mechanisms of HDAC4 involved in mediating biological response, but also form a platform to develop a therapeutic strategy to achieve clinical implications. PMID:24579951

Wang, Zhengke; Qin, Gangjian; Zhao, Ting C.

2015-01-01

7

CD4+ T cell lineage integrity is controlled by the histone deacetylases HDAC1 and HDAC2  

PubMed Central

Molecular mechanisms that maintain lineage integrity of helper T cells are largely unknown. Here we show histone deacetylases (HDAC) 1 and 2 as crucial regulators of this process. Loss of HDAC1 and HDAC2 during late T cell development led to the appearance of MHC class II-selected CD4+ helper T cells (TH) that expressed CD8 lineage genes such as Cd8a and Cd8b1. HDAC1-HDAC2-deficient TH0 and TH1 cells further up-regulated Cd8 lineage genes and acquired a CD8 effector program in a manner dependent on Runx-CBF? complexes, while TH2 cells repressed CD8 lineage features independently of HDAC1 and HDAC2. These results demonstrate that HDAC1-HDAC2 maintain CD4 lineage integrity by repressing Runx-CBF? complexes that otherwise induce a CD8-like effector program in CD4+ T cells. PMID:24681565

Goeschl, Lisa; Moser, Mirjam A.; Lagger, Sabine; Sakaguchi, Shinya; Winter, Mircea; Lenz, Florian; Vitko, Dijana; Breitwieser, Florian P.; Müller, Lena; Hassan, Hammad; Bennett, Keiryn L.; Colinge, Jacques; Schreiner, Wolfgang; Egawa, Takeshi; Taniuchi, Ichiro; Matthias, Patrick; Seiser, Christian; Ellmeier, Wilfried

2015-01-01

8

Human HDAC7 Harbors a Class IIa Histone Deacetylase-specific Zinc Binding Motif and Cryptic Deacetylase Activity  

SciTech Connect

Histone deacetylases (HDACs) are protein deacetylases that play a role in repression of gene transcription and are emerging targets in cancer therapy. Here, we characterize the structure and enzymatic activity of the catalytic domain of human HDAC7 (cdHDAC7). Although HDAC7 normally exists as part of a multiprotein complex, we show that cdHDAC7 has a low level of deacetylase activity which can be inhibited by known HDAC inhibitors. The crystal structures of human cdHDAC7 and its complexes with two hydroxamate inhibitors are the first structures of the catalytic domain of class IIa HDACs and demonstrate significant differences with previously reported class I and class IIb-like HDAC structures. We show that cdHDAC7 has an additional class IIa HDAC-specific zinc binding motif adjacent to the active site which is likely to participate in substrate recognition and protein-protein interaction and may provide a site for modulation of activity. Furthermore, a different active site topology results in modified catalytic properties and in an enlarged active site pocket. Our studies provide mechanistic insights into class IIa HDACs and facilitate the design of specific modulators.

Schuetz, Anja; Min, Jinrong; Allali-Hassani, Abdellah; Schapira, Matthieu; Shuen, Michael; Loppnau, Peter; Mazitschek, Ralph; Kwiatkowski, Nick P.; Lewis, Timothy A.; Maglathin, Rebecca L.; McLean, Thomas H.; Bochkarev, Alexey; Plotnikov, Alexander N.; Vedadi, Masoud; Arrowsmith, Cheryl H. (MIT); (Toronto)

2010-10-18

9

The role of dietary histone deacetylases (HDACs) inhibitors in health and disease.  

PubMed

Modification of the histone proteins associated with DNA is an important process in the epigenetic regulation of DNA structure and function. There are several known modifications to histones, including methylation, acetylation, and phosphorylation, and a range of factors influence each of these. Histone deacetylases (HDACs) remove the acetyl group from lysine residues within a range of proteins, including transcription factors and histones. Whilst this means that their influence on cellular processes is more complex and far-reaching than histone modifications alone, their predominant function appears to relate to histones; through deacetylation of lysine residues they can influence expression of genes encoded by DNA linked to the histone molecule. HDAC inhibitors in turn regulate the activity of HDACs, and have been widely used as therapeutics in psychiatry and neurology, in which a number of adverse outcomes are associated with aberrant HDAC function. More recently, dietary HDAC inhibitors have been shown to have a regulatory effect similar to that of pharmacological HDAC inhibitors without the possible side-effects. Here, we discuss a number of dietary HDAC inhibitors, and how they may have therapeutic potential in the context of a whole food. PMID:25322459

Bassett, Shalome A; Barnett, Matthew P G

2014-10-01

10

Histone Deacetylases  

PubMed Central

In the current era of genomic medicine, diseases are identified as manifestations of anomalous patterns of gene expression. Cancer is the principal example among such maladies. Although remarkable progress has been achieved in the understanding of the molecular mechanisms involved in the genesis and progression of cancer, its epigenetic regulation, particularly histone deacetylation, demands further studies. Histone deacetylases (HDACs) are one of the key players in the gene expression regulation network in cancer because of their repressive role on tumor suppressor genes. Higher expression and function of deacetylases disrupt the finely tuned acetylation homeostasis in both histone and non-histone target proteins. This brings about alterations in the genes implicated in the regulation of cell proliferation, differentiation, apoptosis and other cellular processes. Moreover, the reversible nature of epigenetic modulation by HDACs makes them attractive targets for cancer remedy. This review summarizes the current knowledge of HDACs in tumorigenesis and tumor progression as well as their contribution to the hallmarks of cancer. The present report also describes briefly various assays to detect histone deacetylase activity and discusses the potential role of histone deacetylase inhibitors as emerging epigenetic drugs to cure cancer. PMID:24051359

Parbin, Sabnam; Kar, Swayamsiddha; Shilpi, Arunima; Sengupta, Dipta; Deb, Moonmoon; Rath, Sandip Kumar

2014-01-01

11

Cloning and characterization of a novel human histone deacetylase, HDAC8.  

PubMed Central

Histone deacetylases (HDACs) are a growing family of enzymes implicated in transcriptional regulation by affecting the acetylation state of core histones in the nucleus of cells. HDACs are known to have key roles in the regulation of cell proliferation [Brehm, Miska, McCance, Reid, Bannister and Kouzarides (1998) Nature (London) 391, 597-600], and aberrant recruitment of an HDAC complex has been shown to be a key step in the mechanism of cell transformation in acute promyelocytic leukaemia [Grignani, De Matteis, Nervi, Tomassoni, Gelmetti, Cioce, Fanelli, Ruthardt, Ferrara, Zamir et al. (1998) Nature (London) 391, 815-818; Lin, Nagy, Inoue, Shao, Miller and Evans (1998), Nature (London) 391, 811-814]. Here we present the complete nucleotide sequence of a cDNA clone, termed HDAC8, that encodes a protein product with similarity to the RPD3 class (I) of HDACs. The predicted 377-residue HDAC8 product contains a shorter C-terminal extension relative to other members of its class. After expression in two cell systems, immunopurified HDAC8 is shown to possess trichostatin A- and sodium butyrate-inhibitable HDAC activity on histone H4 peptide substrates as well as on core histones. Expression profiling reveals the expression of HDAC8 to various degrees in every tissue tested and also in several tumour lines. Mutation of two adjacent histidine residues within the predicted active site severely decreases activity, confirming these residues as important for HDAC8 enzyme activity. Finally, linkage analysis after radiation hybrid mapping has localized HDAC8 to chromosomal position Xq21.2-Xq21.3. These results confirm HDAC8 as a new member of the HDAC family. PMID:10926844

Buggy, J J; Sideris, M L; Mak, P; Lorimer, D D; McIntosh, B; Clark, J M

2000-01-01

12

Histone deacetylase 6 (HDAC6) is an essential modifier of glucocorticoid-induced hepatic gluconeogenesis.  

PubMed

In the current study, we investigated the importance of histone deacetylase (HDAC)6 for glucocorticoid receptor-mediated effects on glucose metabolism and its potential as a therapeutic target for the prevention of glucocorticoid-induced diabetes. Dexamethasone-induced hepatic glucose output and glucocorticoid receptor translocation were analyzed in wild-type (wt) and HDAC6-deficient (HDAC6KO) mice. The effect of the specific HDAC6 inhibitor tubacin was analyzed in vitro. wt and HDAC6KO mice were subjected to 3 weeks' dexamethasone treatment before analysis of glucose and insulin tolerance. HDAC6KO mice showed impaired dexamethasone-induced hepatic glucocorticoid receptor translocation. Accordingly, dexamethasone-induced expression of a large number of hepatic genes was significantly attenuated in mice lacking HDAC6 and by tubacin in vitro. Glucose output of primary hepatocytes from HDAC6KO mice was diminished. A significant improvement of dexamethasone-induced whole-body glucose intolerance as well as insulin resistance in HDAC6KO mice compared with wt littermates was observed. This study demonstrates that HDAC6 is an essential regulator of hepatic glucocorticoid-stimulated gluconeogenesis and impairment of whole-body glucose metabolism through modification of glucocorticoid receptor nuclear translocation. Selective pharmacological inhibition of HDAC6 may provide a future therapeutic option against the prodiabetogenic actions of glucocorticoids. PMID:22210316

Winkler, Robin; Benz, Verena; Clemenz, Markus; Bloch, Mandy; Foryst-Ludwig, Anna; Wardat, Sami; Witte, Nicole; Trappiel, Manuela; Namsolleck, Pawel; Mai, Knut; Spranger, Joachim; Matthias, Gabriele; Roloff, Tim; Truee, Oliver; Kappert, Kai; Schupp, Michael; Matthias, Patrick; Kintscher, Ulrich

2012-02-01

13

Divergent roles of histone deacetylase 6 (HDAC6) and histone deacetylase 11 (HDAC11) on the transcriptional regulation of IL10 in antigen presenting cells.  

PubMed

The anti-inflammatory cytokine IL-10 is a key modulator of immune responses. A better understanding of the regulation of this cytokine offers the possibility of tipping the balance of the immune response toward either tolerance, or enhanced immune responses. Histone deacetylases (HDACs) have been widely described as negative regulators of transcriptional regulation, and in this context, the primarily nuclear protein HDAC11 was shown to repress il-10 gene transcriptional activity in antigen-presenting cells (APCs). Here we report that another HDAC, HDAC6, primarily a cytoplasmic protein, associates with HDAC11 and modulates the expression of IL-10 as a transcriptional activator. To our knowledge, this is the first demonstration of two different HDACs being recruited to the same gene promoter to dictate divergent transcriptional responses. This dynamic interaction results in dynamic changes in the expression of IL-10 and might help to explain the intrinsic plasticity of the APC to determine T-cell activation versus T-cell tolerance. PMID:24747960

Cheng, Fengdong; Lienlaf, Maritza; Perez-Villarroel, Patricio; Wang, Hong-Wei; Lee, Calvin; Woan, Karrune; Woods, David; Knox, Tessa; Bergman, Joel; Pinilla-Ibarz, Javier; Kozikowski, Alan; Seto, Edward; Sotomayor, Eduardo M; Villagra, Alejandro

2014-07-01

14

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

15

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

16

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

17

c-Abl induces stabilization of histone deacetylase 1 (HDAC1) in a kinase activity-dependent manner.  

PubMed

c-Abl is a non-receptor-type tyrosine kinase that regulates various cellular events, including cell proliferation, differentiation, and apoptosis, through phosphorylation of cytoplasmic and nuclear targets. Although we showed that c-Abl induces histone deacetylation, the molecular mechanisms of this phenomenon are largely unknown. Here, we analyzed the effect of c-Abl on the expression of histone deacetylase 1 (HDAC1), because c-Abl was shown to be involved in maintenance of nuclear protein levels of HDAC1. Co-transfection of HDAC1 with c-Abl increased the levels of HDAC1 protein in a kinase activity-dependent manner without affecting its mRNA levels. Treatment with the proteasome inhibitor MG132 increased protein levels of HDAC1 in cells transfected with HDAC1 but not in cells co-transfected with HDAC1 and c-Abl. Among class I HDACs, knockdown of endogenous c-Abl preferentially suppressed endogenous protein levels of HDAC1, suggesting that c-Abl stabilizes HDAC1 protein by inhibiting its proteasomal degradation. Subcellular fractionation showed that the stabilization of HDAC1 by c-Abl occurred in the nucleus. Despite the fact that HDAC1 was phosphorylated by co-expression with c-Abl, stabilization of HDAC1 by c-Abl was not affected by mutations in its sites phosphorylated by c-Abl. Co-expression with HDAC1 and nuclear-targeted c-Abl did not affect HDAC1 stabilization. Therefore, these results suggest that c-Abl induces HDAC1 stabilization possibly through phosphorylation of a cytoplasmic target that is involved in proteasomal degradation of HDAC1. PMID:25561363

Aoyama, Kazumasa; Yamaguchi, Noritaka; Yuki, Ryuzaburo; Morii, Mariko; Kubota, Sho; Hirata, Kensuke; Abe, Kohei; Honda, Takuya; Kuga, Takahisa; Hashimoto, Yuuki; Tomonaga, Takeshi; Yamaguchi, Naoto

2015-04-01

18

Molecular identification of PpHDAC1, the first histone deacetylase fron the slime mold Physarum polycephalum.  

PubMed

The dynamic state of post-translational acetylation of eukaryotic histones is maintained by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HATs and HDACs have been shown to be components of various regulatory protein complexes in the cell. Their enzymatic activities, intracellular localization and substrate specificities are regulated in a complex, cell cycle related manner. In the myxomycete Physarum polycephalum multiple HATs and HDACs can be distinguished in biochemical terms and they exhibit dynamic activity patterns depending on the cell cycle stage. Here we report on the cloning of the first P. polycephalum HDAC (PpHDAC1) related to the S. cerevisiae Rpd3 protein. The expression pattern of PpHDAC1 mRNA was analysed at different time points of the cell cycle and found to be largely constant. Treatment of macroplasmodia with the HDAC inhibitor trichostatin A at several cell cycle stages resulted in a significant delay in entry into mitosis of treated versus untreated plasmodia. No effect of TSA treatment could be observed on PpHDAC1 expression itself. PMID:12377210

Brandtner, Eva-Maria; Lechner, Thomas; Loidl, Peter; Lusser, Alexandra

2002-01-01

19

Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor  

PubMed Central

Histone deacetylases (HDACs) are a family of enzymes involved in the regulation of gene expression, DNA repair, and stress response. These processes often are altered in tumors, and HDAC inhibitors have had pronounced antitumor activity with promising results in clinical trials. Here, we report the crystal structure of human HDAC8 in complex with a hydroxamic acid inhibitor. Such a structure of a eukaryotic zinc-dependent HDAC has not be described previously. Similar to bacterial HDAC-like protein, HDAC8 folds in a single ?/? domain. The inhibitor and the zinc-binding sites are similar in both proteins. However, significant differences are observed in the length and structure of the loops surrounding the active site, including the presence of two potassium ions in HDAC8 structure, one of which interacts with key catalytic residues. CD data suggest a direct role of potassium in the fold stabilization of HDAC8. Knockdown of HDAC8 by RNA interference inhibits growth of human lung, colon, and cervical cancer cell lines, highlighting the importance of this HDAC subtype for tumor cell proliferation. Our findings open the way for the design and development of selective inhibitors of HDAC8 as possible antitumor agents. PMID:15477595

Vannini, Alessandro; Volpari, Cinzia; Filocamo, Gessica; Casavola, Elena Caroli; Brunetti, Mirko; Renzoni, Debora; Chakravarty, Prasun; Paolini, Chantal; De Francesco, Raffaele; Gallinari, Paola; Steinkühler, Christian; Di Marco, Stefania

2004-01-01

20

Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor.  

PubMed

Histone deacetylases (HDACs) are a family of enzymes involved in the regulation of gene expression, DNA repair, and stress response. These processes often are altered in tumors, and HDAC inhibitors have had pronounced antitumor activity with promising results in clinical trials. Here, we report the crystal structure of human HDAC8 in complex with a hydroxamic acid inhibitor. Such a structure of a eukaryotic zinc-dependent HDAC has not be described previously. Similar to bacterial HDAC-like protein, HDAC8 folds in a single alpha/beta domain. The inhibitor and the zinc-binding sites are similar in both proteins. However, significant differences are observed in the length and structure of the loops surrounding the active site, including the presence of two potassium ions in HDAC8 structure, one of which interacts with key catalytic residues. CD data suggest a direct role of potassium in the fold stabilization of HDAC8. Knockdown of HDAC8 by RNA interference inhibits growth of human lung, colon, and cervical cancer cell lines, highlighting the importance of this HDAC subtype for tumor cell proliferation. Our findings open the way for the design and development of selective inhibitors of HDAC8 as possible antitumor agents. PMID:15477595

Vannini, Alessandro; Volpari, Cinzia; Filocamo, Gessica; Casavola, Elena Caroli; Brunetti, Mirko; Renzoni, Debora; Chakravarty, Prasun; Paolini, Chantal; De Francesco, Raffaele; Gallinari, Paola; Steinkühler, Christian; Di Marco, Stefania

2004-10-19

21

Histone Deacetylase 1  

Microsoft Academic Search

HDAC1 was the first histone deacetylase identified in mammals and is considered the prototype of this large family of enzymes.\\u000a Transcriptional repression mediated by HDAC1 plays a crucial role in the regulation of a variety of biological processes,\\u000a including cell cycle progression, proliferation, and differentiation. Interestingly, HDAC1 can also influence other cellular\\u000a activities, such as DNA replication and chromosome segregation,

Dominique Meunier; Christian Seiser

22

Valproic Acid as a Potential Inhibitor of Plasmodium falciparum Histone Deacetylase 1 (PfHDAC1): An in Silico Approach  

PubMed Central

A new Plasmodium falciparum histone deacetylase1 (PfHDAC1) homology model was built based on the highest sequence identity available template human histone deacetylase 2 structure. The generated model was carefully evaluated for stereochemical accuracy, folding correctness and overall structure quality. All evaluations were acceptable and consistent. Docking a group of hydroxamic acid histone deacetylase inhibitors and valproic acid has shown binding poses that agree well with inhibitor-bound histone deacetylase-solved structural interactions. Docking affinity dG scores were in agreement with available experimental binding affinities. Further, enzyme-ligand complex stability and reliability were investigated by running 5-nanosecond molecular dynamics simulations. Thorough analysis of the simulation trajectories has shown that enzyme-ligand complexes were stable during the simulation period. Interestingly, the calculated theoretical binding energies of the docked hydroxamic acid inhibitors have shown that the model can discriminate between strong and weaker inhibitors and agrees well with the experimental affinities reported in the literature. The model and the docking methodology can be used in screening virtual libraries for PfHDAC1 inhibitors, since the docking scores have ranked ligands in accordance with experimental binding affinities. Valproic acid calculated theoretical binding energy suggests that it may inhibit PfHDAC1. PMID:25679451

Elbadawi, Mohamed A. Abdallah; Awadalla, Mohamed Khalid Alhaj; Abdel Hamid, Muzamil Mahdi; Mohamed, Magdi Awadalla; Awad, Talal Ahmed

2015-01-01

23

Extracellular Signal-regulated Kinase (ERK) Phosphorylates Histone Deacetylase 6 (HDAC6) at Serine 1035 to Stimulate Cell Migration*  

PubMed Central

Histone deacetylase 6 (HDAC6) is well known for its ability to promote cell migration through deacetylation of its cytoplasmic substrates such as ?-tubulin. However, how HDAC6 itself is regulated to control cell motility remains elusive. Previous studies have shown that one third of extracellular signal-regulated kinase (ERK) is associated with the microtubule cytoskeleton in cells. Yet, no connection between HDAC6 and ERK has been discovered. Here, for the first time, we reveal that ERK binds to and phosphorylates HDAC6 to promote cell migration via deacetylation of ?-tubulin. We have identified two novel ERK-mediated phosphorylation sites: threonine 1031 and serine 1035 in HDAC6. Both sites were phosphorylated by ERK1 in vitro, whereas Ser-1035 was phosphorylated in response to the activation of EGFR-Ras-Raf-MEK-ERK signaling pathway in vivo. HDAC6-null mouse embryonic fibroblasts rescued by the nonphosphorylation mimicking mutant displayed significantly reduced cell migration compared with those rescued by the wild type. Consistently, the nonphosphorylation mimicking mutant exerted lower tubulin deacetylase activity in vivo compared with the wild type. These data indicate that ERK/HDAC6-mediated cell motility is through deacetylation of ?-tubulin. Overall, our results suggest that HDAC6-mediated cell migration could be governed by EGFR-Ras-Raf-MEK-ERK signaling. PMID:24089523

Williams, Kendra A.; Zhang, Mu; Xiang, Shengyan; Hu, Chen; Wu, Jheng-Yu; Zhang, Shengping; Ryan, Meagan; Cox, Adrienne D.; Der, Channing J.; Fang, Bin; Koomen, John; Haura, Eric; Bepler, Gerold; Nicosia, Santo V.; Matthias, Patrick; Wang, Chuangui; Bai, Wenlong; Zhang, Xiaohong

2013-01-01

24

Histone Deacetylase (HDAC) Inhibitor Kinetic Rate Constants Correlate with Cellular Histone Acetylation but Not Transcription and Cell Viability  

PubMed Central

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

2013-01-01

25

Histone deacetylases in viral infections  

Microsoft Academic Search

Chromatin remodeling and gene expression are regulated by histone deacetylases (HDACs) that condense the chromatin structure\\u000a by deacetylating histones. HDACs comprise a group of enzymes that are responsible for the regulation of both cellular and\\u000a viral genes at the transcriptional level. In mammals, a total of 18 HDACs have been identified and grouped into four classes,\\u000a i.e., class I (HDACs

Georges Herbein; Daniel Wendling

2010-01-01

26

Inhibition of Histone Deacetylases  

PubMed Central

Lysine acetylation of histones is one of the major epigenetic regulators of chromatin conformation and gene expression. The dynamic nature of histone acetylation is determined by the counterbalancing activity of histone acetyltransferase and histone deacetylase (HDAC) enzymes. Acetylation of histones is generally associated with open and transcriptionally active chromatin, whereas the activity of HDACs leads to histone deacetylation, condensation of chromatin, and inhibition of transcription. Aberrant silencing of tumor suppressors and other genes has been found in different types of cancer. Abnormal activity of HDACs has been implicated in tumorigenesis and therefore considerable effort has been put into the development of HDAC inhibitors as a means of modifying histone acetylation status and reexpressing aberrantly silenced tumor suppressor genes. This has led to the generation of a number of structurally diverse compounds that can effectively inhibit HDAC activity, thus altering chromatin structure in cancer cells. This unit discusses the methods and recent technological developments with respect to the studies of HDAC inhibition in cancer. PMID:15273406

Huang, Yi; Shaw, Patrick G.; Davidson, Nancy E.

2013-01-01

27

Santacruzamate A, a Potent and Selective Histone Deacetylase (HDAC) Inhibitor from the Panamanian Marine Cyanobacterium cf. Symploca sp.  

PubMed Central

A dark-brown tuft-forming cyanobacterium, morphologically resembling the genus Symploca, was collected during an expedition to the Coiba National Park, a UNESCO World Heritage Site on the Pacific coast of Panama. Phylogenetic analysis of its 16S rRNA gene sequence indicated that it is 4.5% divergent from the type strain for Symploca, and thus is likely a new genus. Fractionation of the crude extract led to the isolation of a new cytotoxin, designated santacruzamate A (1), which has several structural features in common with suberoylanilide hydroxamic acid [(2), SAHA, trade name Vorinostat®], a clinically approved histone deacetylase (HDAC) inhibitor used to treat refractory cutaneous T-cell lymphoma. Recognition of the structural similarly of 1 and SAHA led to the characterization of santacruzamate A as a picomolar level selective inhibitor of HDAC2, a Class I HDAC, with relatively little inhibition of HDAC4 or HDAC6, both Class II HDACs. As a result, chemical syntheses of santacruzamate A as well as a structurally intriguing hybrid molecule, which blends aspects of both agents (1 and 2), were achieved and evaluated for their HDAC activity and specificity. PMID:24164245

Pavlik, Christopher M.; Wong, Christina Y.B.; Ononye, Sophia; Lopez, Dioxelis D.; Engene, Niclas; McPhail, Kerry L.; Gerwick, William H.; Balunas, Marcy J.

2013-01-01

28

Preclinical antitumor activity of ST7612AA1: a new oral thiol-based histone deacetylase (HDAC) inhibitor.  

PubMed

ST7612AA1 (property of Sigma-Tau), a thioacetate-? (?-lactam amide) derivative, is a potent, second generation, oral pan-histone deacetylase inhibitor (HDACi). Aim of the study was to assess the efficacy of ST7612AA1 in solid and haematological tumors, and to characterize its mechanism of action. In vitro, ST7612AA1 potently inhibited different class I and class II HDACs, leading to restore the balance of both histone and non-histone protein acetylation. In vivo, it induced significant anti-tumor effects in xenograft models of lung, colon, breast and ovarian carcinomas, leukemia and lymphoma. This was likely due to the modulation of different HDAC substrates and induction of transcriptional changes with respect to several genes involved in key processes, such as cell cycle regulation, DNA damage checkpoints, immune response, cell adhesion and epithelial-to-mesenchymal transition. PK analysis confirmed the pro-drug nature of ST7612AA1, which is rapidly absorbed and converted to ST7464AA1 after a single oral dose in mice. ST7612AA1 was selected from a novel generation of oral HDAC inhibitors. Its high efficacy correlated with its potent and selective inhibitory activity of HDAC and was combined with a favorable pharmacodynamics profile. These aspects support a clinical development of ST7612AA1 towards a broad spectrum of human solid and haematologic malignancies. PMID:25671299

Vesci, Loredana; Bernasconi, Elena; Milazzo, Ferdinando Maria; De Santis, Rita; Gaudio, Eugenio; Kwee, Ivo; Rinaldi, Andrea; Pace, Silvia; Carollo, Valeria; Giannini, Giuseppe; Bertoni, Francesco

2015-03-20

29

Restoring Histone Deacetylase Activity by Waste Product Release. A View from Molecular Mechanics Simulations with Mammalian HDAC8.  

PubMed

HDAC8 is a Zn(II) -based, single-peptide mammalian histone deacetylase that is localized mainly in the cytoskeleton of smooth muscle cells, thus regulating muscle contractility. HDACs are also widely involved in cellular processes, ranging from cell differentiation to proliferation, senescence, and apoptosis; in particular, protecting a telomerase activator from ubiquitin-mediated degradation. How HDACs can eliminate the hydrolytic reaction products, in order that the process of deacetylation of the acetyllysine moiety of histones can take place again, has long been debated in the scientific literature, without reaching any firm conclusion, however. This question is the subject of the present work, carried out along a theoretical line that is capable of describing the whole pathway followed by the acetate product (ACT). A model was built here on the crystal data for the Y306F-mutated HDAC8 complex with a diacetylated peptide of the p53-tumor-suppressor class. That was followed by manually hydrolyzing the acetylated moiety bound to Zn(II) and discharging the monoacetylated peptide product (MAP). The latter was replaced by a H2 O molecule bound to Zn(II) , while ACT was left free in the reaction cage. This Zn(II) cluster was DFT-parameterized for the ff99SB force field without any further bias. As the result of random-acceleration molecular dynamics (RAMD) simulations, egress of ACT from the reaction cage toward the aqueous environment can follow three pathways. Two of them utilize the channel for peptide (or histone) uptake and are preferred, if ACT leaves the reaction center before MAP (or the deacetylated histone). The third pathway, developing along the internal channel, is available to ACT even if MAP is still in place. PMID:25879496

Pietra, Francesco

2015-04-01

30

Design, synthesis, and biological evaluation of potent and selective class IIa histone deacetylase (HDAC) inhibitors as a potential therapy for Huntington's disease.  

PubMed

Inhibition of class IIa histone deacetylase (HDAC) enzymes have been suggested as a therapeutic strategy for a number of diseases, including Huntington's disease. Catalytic-site small molecule inhibitors of the class IIa HDAC4, -5, -7, and -9 were developed. These trisubstituted diarylcyclopropanehydroxamic acids were designed to exploit a lower pocket that is characteristic for the class IIa HDACs, not present in other HDAC classes. Selected inhibitors were cocrystallized with the catalytic domain of human HDAC4. We describe the first HDAC4 catalytic domain crystal structure in a "closed-loop" form, which in our view represents the biologically relevant conformation. We have demonstrated that these molecules can differentiate class IIa HDACs from class I and class IIb subtypes. They exhibited pharmacokinetic properties that should enable the assessment of their therapeutic benefit in both peripheral and CNS disorders. These selective inhibitors provide a means for evaluating potential efficacy in preclinical models in vivo. PMID:24261862

Bürli, Roland W; Luckhurst, Christopher A; Aziz, Omar; Matthews, Kim L; Yates, Dawn; Lyons, Kathy A; Beconi, Maria; McAllister, George; Breccia, Perla; Stott, Andrew J; Penrose, Stephen D; Wall, Michael; Lamers, Marieke; Leonard, Philip; Müller, Ilka; Richardson, Christine M; Jarvis, Rebecca; Stones, Liz; Hughes, Samantha; Wishart, Grant; Haughan, Alan F; O'Connell, Catherine; Mead, Tania; McNeil, Hannah; Vann, Julie; Mangette, John; Maillard, Michel; Beaumont, Vahri; Munoz-Sanjuan, Ignacio; Dominguez, Celia

2013-12-27

31

Histone deacetylase (HDAC) Inhibitors Preserve White Matter Structure and Function During Ischemia by Conserving ATP and Reducing Excitotoxicity  

PubMed Central

The importance of white matter (WM) injury to stroke pathology has been underestimated in experimental animal models and this may have contributed to the failure to translate potential therapeutics into the stroke clinic. Histone deacetylase (HDAC) inhibitors are neuroprotective and also promote neurogenesis. These properties make them ideal candidates for stroke therapy. In a pure WM tract (isolated mouse optic nerve) we show that pan- and Class I specific HDAC inhibitors, administered before or after a period of oxygen and glucose deprivation (OGD), promote functional recovery of axons and preserve WM cellular architecture. This protection correlates with the up-regulation of an astrocyte glutamate transporter, delayed and reduced glutamate accumulation during OGD, preservation of axonal mitochondria and oligodendrocytes, and maintenance of ATP levels. Interestingly, the expression of HDACs 1, 2 and 3 is localized to astrocytes, suggesting that changes in glial cell gene transcription and/or protein acetylation may confer protection to axons. Our findings suggest that a therapeutic opportunity exists for the use of HDAC inhibitors, targeting mitochondrial energy regulation and excitotoxicity in ischemic WM injury. PMID:21411642

Baltan, Selva; Murphy, Sean P.; Danilov, Camelia A.; Bachleda, Amelia; Morrison, Richard S.

2011-01-01

32

Mechanism of N-Acylthiourea-mediated Activation of Human Histone Deacetylase 8 (HDAC8) at Molecular and Cellular Levels.  

PubMed

We reported previously that an N-acylthiourea derivative (TM-2-51) serves as a potent and isozyme-selective activator for human histone deacetylase 8 (HDAC8). To probe the molecular mechanism of the enzyme activation, we performed a detailed account of the steady-state kinetics, thermodynamics, molecular modeling, and cell biology studies. The steady-state kinetic data revealed that TM-2-51 binds to HDAC8 at two sites in a positive cooperative manner. Isothermal titration calorimetric and molecular modeling data conformed to the two-site binding model of the enzyme-activator complex. We evaluated the efficacy of TM-2-51 on SH-SY5Y and BE(2)-C neuroblastoma cells, wherein the HDAC8 expression has been correlated with cellular malignancy. Whereas TM-2-51 selectively induced cell growth inhibition and apoptosis in SH-SY5Y cells, it showed no such effects in BE(2)-C cells, and this discriminatory feature appears to be encoded in the p53 genotype of the above cells. Our mechanistic and cellular studies on HDAC8 activation have the potential to provide insight into the development of novel anticancer drugs. PMID:25605725

Singh, Raushan K; Cho, Kyongshin; Padi, Satish K R; Yu, Junru; Haldar, Manas; Mandal, Tanmay; Yan, Changhui; Cook, Gregory; Guo, Bin; Mallik, Sanku; Srivastava, D K

2015-03-01

33

Macrocyclic Histone Deacetylase Inhibitors  

PubMed Central

Histone deacetylase inhibitors (HDACi) are an emerging class of novel anti-cancer drugs that cause growth arrest, differentiation, and apoptosis of tumor cells. In addition, they have shown promise as anti-parasitic, anti-neurodegenerative, anti-rheumatologic and immunosuppressant agents. To date, several structurally distinct small molecule HDACi have been reported including aryl hydroxamates, benzamides, short-chain fatty acids, electrophilic ketones, and macrocyclic peptides. Macrocyclic HDACi possess the most complex cap-groups which interact with HDAC enzyme’s outer rim and have demonstrated excellent HDAC inhibition potency and isoform selectivity. This review focuses on the recent progress and current state of macrocyclic HDACi. PMID:20536416

Mwakwari, Sandra C.; Patil, Vishal; Guerrant, William; Oyelere, Adegboyega K.

2011-01-01

34

The interplay between G protein-coupled receptor kinase 2 (GRK2) and histone deacetylase 6 (HDAC6) at the crossroads of epithelial cell motility  

PubMed Central

G protein-coupled receptor kinase 2 (GRK2) is emerging as a key integrative node in cell migration control. In addition to its canonical role in the desensitization of G protein-coupled receptors involved in chemotaxis, novel recently identified GRK2 substrates and interacting partners appear to mediate the GRK2-dependent modulation of diverse molecular processes involved in motility, such as gradient sensing, cell polarity or cytoskeletal reorganization. We have recently identified an interaction between GRK2 and histone deacetylase 6 (HDAC6), a major cytoplasmic ?-tubulin deacetylase involved in cell motility and adhesion. GRK2 dynamically associates with and phosphorylates HDAC6 to stimulate its ?-tubulin deacetylase activity at specific cellular localizations such as the leading edge of migrating cells, thus promoting local tubulin deacetylation and enhanced motility. This GRK2-HDAC6 functional interaction may have important implications in pathological contexts related to aberrant epithelial cell migration. PMID:23076141

Lafarga, Vanesa; Mayor, Jr, Federico; Penela, Petronila

2012-01-01

35

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

36

Peptide Mass Mapping of Acetylated Isoforms of Histone H4 from Mouse Lymphosarcoma Cells Treated with Histone Deacetylase (HDACs) Inhibitors  

PubMed Central

The acetylated isoforms of histone H4 from mouse lymphosarcoma cells treated with HDAC inhibitors trichostatin A (TSA) and depsipeptide (DDP) were separated by acetic acid urea-polyacrylamide gel electrophoresis (AU-PAGE), in-gel digested, and analyzed by matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and liquid chromatography tandem mass spectrometry (LC-MS/MS). The acetylation pattern of histone H4 in mouse lymphosarcoma cells induced by TSA was established in which acetylation initially occurred at K16 followed by K12 and then K8 and/or K5. An identical order of acetylation was found for cells treated with DDP. PMID:16099169

Ren, Chen; Zhang, Liwen; Freitas, Michael A.; Ghoshal, Kalpana; Parthun, Mark R.; Jacob, Samson T.

2009-01-01

37

Anticancer activities of histone deacetylase inhibitors  

Microsoft Academic Search

Histone deacetylases (HDACs) are enzymes involved in the remodelling of chromatin, and have a key role in the epigenetic regulation of gene expression. In addition, the activity of non-histone proteins can be regulated through HDAC-mediated hypo-acetylation. In recent years, inhibition of HDACs has emerged as a potential strategy to reverse aberrant epigenetic changes associated with cancer, and several classes of

Jessica E. Bolden; Melissa J. Peart; Ricky W. Johnstone

2006-01-01

38

Histone deacetylase (HDAC) inhibitors with a novel connecting unit linker region reveal a selectivity profile for HDAC4 and HDAC5 with improved activity against chemoresistant cancer cells.  

PubMed

The synthesis and biological evaluation of new potent hydroxamate-based HDAC inhibitors with a novel alkoxyamide connecting unit linker region are described. Biological evaluation includes MTT and cellular HDAC assays on sensitive and chemoresistant cancer cell lines as well as HDAC profiling of selected compounds. Compound 19i (LMK235) (N-((6-(hydroxyamino)-6-oxohexyl)oxy)-3,5-dimethylbenzamide) showed similar effects compared to vorinostat on inhibition of cellular HDACs in a pan-HDAC assay but enhanced cytotoxic effects against the human cancer cell lines A2780, Cal27, Kyse510, and MDA-MB231. Subsequent HDAC profiling yielded a novel HDAC isoform selectivity profile of 19i in comparison to vorinostat or trichostatin A (TSA). 19i shows nanomolar inhibition of HDAC4 and HDAC5, whereas vorinostat and TSA inhibit HDAC4 and HDAC5 in the higher micromolar range. PMID:23252603

Marek, Linda; Hamacher, Alexandra; Hansen, Finn K; Kuna, Krystina; Gohlke, Holger; Kassack, Matthias U; Kurz, Thomas

2013-01-24

39

Lithium Down-regulates Histone Deacetylase 1 (HDAC1) and Induces Degradation of Mutant Huntingtin*  

PubMed Central

Lithium is an effective mood stabilizer that has been clinically used to treat bipolar disorder for several decades. Recent studies have suggested that lithium possesses robust neuroprotective and anti-tumor properties. Thus far, a large number of lithium targets have been discovered. Here, we report for the first time that HDAC1 is a target of lithium. Lithium significantly down-regulated HDAC1 at the translational level by targeting HDAC1 mRNA. We also showed that depletion of HDAC1 is essential for the neuroprotective effects of lithium and for the lithium-mediated degradation of mutant huntingtin through the autophagic pathway. Our studies explain the multiple functions of lithium and reveal a novel mechanism for the function of lithium in neurodegeneration. PMID:24165128

Wu, Shuai; Zheng, Shui-Di; Huang, Hong-Ling; Yan, Li-Chong; Yin, Xiao-Fei; Xu, Hai-Neng; Zhang, Kang-Jian; Gui, Jing-Hua; Chu, Liang; Liu, Xin-Yuan

2013-01-01

40

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

41

Nuclear histone acetylases and deacetylases and transcriptional regulation: HATs off to HDACs  

Microsoft Academic Search

Reversible acetylation of lysines on the amino-terminal tails of nucleosomal histones is correlated with changes in chromatin structure and transcription. The recent characterization of enzymes directly responsible for regulating histone acetylation and deacetylation and the cloning of their encoding cDNAs have provided insights into the possible functional and regulatory mechanisms of these classes of molecules. Nuclear histone acetylases have been

Christian A Hassig; Stuart L Schreiber

1997-01-01

42

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

43

Histone Deacetylase 2 (HDAC2) Protein-dependent Deacetylation of Mortality Factor 4-like 1 (MORF4L1) Protein Enhances Its Homodimerization*  

PubMed Central

Histone acetyltransferase mortality factor 4-like 1 (MORF4L1) is a relatively new histone acetyltransferase component that exists as a homodimer to exert its epigenetic function. The mechanism of MORF4L1 self-assembly is unknown. Here we report that Lys-148 deacetylation is indispensable for facilitating MORF4L1 self-assembly into a homodimeric unit. Among a stretch of ?10 amino acids in the NH2 terminus between the chromodomain and MORF4-related gene (MRG) domain within MORF4L1, Lys-148 is normally acetylated. Substitution of Lys-148 with arginine augments MORF4L1 self-assembly. However, acetylation mimics of MORF4L1, including K148L and K148Q, abolished its self-assembly of the histone acetyltransferase component. HDAC2, a deacetylase, interacts with and keeps MORF4L1 in a deacetylation status at Lys148 that triggers MORF4L1 self-assembly. Knockdown of HDAC2 reduces MORF4L1 self-assembly. HDAC2-dependent deacetylation of MORF4L1 enhances MORF4L1 homodimerization, thus facilitating the functionality of complex formation to repress cell proliferation. PMID:24451372

Chen, Yan; Li, Jin; Dunn, Sarah; Xiong, Sheng; Chen, Wei; Zhao, Yutong; Chen, Bill B.; Mallampalli, Rama K.; Zou, Chunbin

2014-01-01

44

Rho-kinase signaling controls nucleocytoplasmic shuttling of class IIa Histone Deacetylase (HDAC7) and transcriptional activation of orphan nuclear receptor NR4A1.  

PubMed

Rho-kinase (ROCK) has been well documented to play a key role in RhoA-induced actin remodeling. ROCK activation results in myosin light chain (MLC) phosphorylation either by direct action on MLC kinase (MLCK) or by inhibition of MLC phosphatase (MLCP), modulating actin-myosin contraction. We found that inhibition of the ROCK pathway in induced pluripotent stem cells, leads to nuclear export of HDAC7 and transcriptional activation of the orphan nuclear receptor NR4A1 while in cells with constitutive ROCK hyperactivity due to loss of function of the RhoGTPase activating protein Oligophrenin-1 (OPHN1), the orphan nuclear receptor NR4A1 is downregulated. Our study identify a new target of ROCK signaling via myosin phosphatase subunit (MYPT1) and Histone Deacetylase (HDAC7) at the nuclear level and provide new insights in the cellular functions of ROCK. PMID:25511694

Compagnucci, Claudia; Barresi, Sabina; Petrini, Stefania; Bertini, Enrico; Zanni, Ginevra

2015-04-01

45

OSU-HDAC42, a histone deacetylase inhibitor, blocks prostate tumor progression in the transgenic adenocarcinoma of the mouse prostate model.  

PubMed

Histone deacetylase (HDAC) inhibitors suppress tumor cell growth via a broad spectrum of mechanisms, which should prove advantageous in the context of cancer prevention. Here, we examined the effect of dietary administration of OSU-HDAC42, a novel HDAC inhibitor, on prostate tumor progression in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Based on a series of pilot studies, an AIN-76A diet was formulated containing 208 ppm OSU-HDAC42, which was estimated to deliver approximately 25 mg/kg of drug per day to each mouse and found to cause a suppression of PC-3 xenograft tumor growth equivalent to that achieved by gavage administration of a similar dose. At 6 weeks of age, TRAMP mice received this drug-containing or control diet for 4 or 18 weeks and were evaluated for prostatic intraepithelial neoplasia (PIN) and carcinoma development, respectively. OSU-HDAC42 not only decreased the severity of PIN and completely prevented its progression to poorly differentiated carcinoma (74% incidence in controls versus none in drug-treated mice), but also shifted tumorigenesis to a more differentiated phenotype, suppressing absolute and relative urogenital tract weights by 86% and 85%, respectively, at 24 weeks of age. This tumor suppression was associated with the modulation of intraprostatic biomarkers, including those indicative of HDAC inhibition, increased apoptosis and differentiation, and decreased proliferation. With the exception of completely reversible hematologic alterations and testicular degeneration, no significant changes in body weight or other indicators of general health were observed in drug-treated mice. These results suggest that OSU-HDAC42 has value in prostate cancer prevention. [Cancer Res 2008;68(10):3999-4009]. PMID:18483287

Sargeant, Aaron M; Rengel, Robert C; Kulp, Samuel K; Klein, Russell D; Clinton, Steven K; Wang, Yu-Chieh; Chen, Ching-Shih

2008-05-15

46

Phase I clinical, pharmacokinetic and pharmacodynamic study of SB939, an oral histone deacetylase (HDAC) inhibitor, in patients with advanced solid tumours  

PubMed Central

Background: SB939 is an orally available, competitive histone deacetylase (HDAC) inhibitor selective for class I, II and IV histone deacetylases. Preclinical evaluation of SB939 revealed a profile suggesting improved efficacy compared to other HDAC inhibitors. This phase I study was carried out to determine the safety, dose-limiting toxicity, recommended phase II dose (RPTD), as well as pharmacokinetic (PK) and pharmacodynamic (PD) profiles of SB939 in a daily × 5 schedule in advanced solid tumours. Methods: Sequential dose-escalating cohorts of patients were enrolled into 8 dose levels. At dose level 1, SB939 was taken on days 1–3 and 15–17 every 4 weeks, then on days 1–5 and 15–19 for other dose levels. Detailed PK sampling was performed in cycle 1, days 1 and 5. Peripheral blood mononuclear cells (PBMCs) were collected on cycle 1 at various time points for determination of acetylated histone H3 (AcH3) levels. Results: In total, 38 patients received a total of 96 cycles of treatment. The maximal administered dose was 90?mg and the RPTD was 60?mg given 5 consecutive days every 2 weeks. The most frequent non-hematologic adverse events (AEs) of at least possible attribution to SB939 were fatigue, nausea, vomiting, anorexia and diarrhoea. Pharmacokinetic analysis showed dose-proportional increases in AUC across the doses evaluated. Elimination half-life was 5.6–8.9?h. There was no clear relationship between AcH3 changes and dose level or anti-tumour response. Conclusions: SB939 is well tolerated in patients with advanced solid tumours. The RPTD of this drug is 60?mg on a schedule of 5 consecutive days every 2 weeks. The toxicities of SB939 are consistent with other HDAC inhibitors. PMID:21285985

Razak, A R A; Hotte, S J; Siu, L L; Chen, E X; Hirte, H W; Powers, J; Walsh, W; Stayner, L-A; Laughlin, A; Novotny-Diermayr, V; Zhu, J; Eisenhauer, E A

2011-01-01

47

Physiological Roles of Class I HDAC Complex and Histone Demethylase  

PubMed Central

Epigenetic gene silencing is one of the fundamental mechanisms for ensuring proper gene expression patterns during cellular differentiation and development. Histone deacetylases (HDACs) are evolutionally conserved enzymes that remove acetyl modifications from histones and play a central role in epigenetic gene silencing. In cells, HDAC forms a multiprotein complex (HDAC complex) in which the associated proteins are believed to help HDAC carry out its cellular functions. Though each HDAC complex contains distinct components, the presence of isoforms for some of the components expands the variety of complexes and the diversity of their cellular roles. Recent studies have also revealed a functional link between HDAC complexes and specific histone demethylases. In this paper, we summarize the distinct and cooperative roles of four class I HDAC complexes, Sin3, NuRD, CoREST, and NCoR/SMRT, with respect to their component diversity and their relationship with specific histone demethylases. PMID:21049000

Hayakawa, Tomohiro; Nakayama, Jun-ichi

2011-01-01

48

Histone Deacetylase and DNA Methyltransferase in Human Prostate Cancer  

Microsoft Academic Search

CpG island hypermethylation and chromatin remodeling play important roles in repression of various genes during malignant transformation. We hypothesized that histone deacetylases (HDACs) and DNA methyltransferases (DNMTase) are associated with prostate cancer and we examined the enzyme activity, gene, and protein expression of HDAC1 and DNMT1 in cell lines and tissues. We found that DNMTase and HDACs activities were two-

Samir K. Patra; Aditi Patra; Rajvir Dahiya

2001-01-01

49

Histone Deacetylase 8i n NeuroblastomaTumorigenesis  

Microsoft Academic Search

Purpose: The effects of pan ^ histone deacetylase (HDAC) inhibitors on cancer cells have shown that HDACs are involved in fundamental tumor biological processes such as cell cycle control, differentiation, and apoptosis. However, because of the unselective nature of these compounds, little is known about the contribution of individual HDAC family members to tumorigenesis and progression. The purpose of this

Ina Oehme; Hedwig E. Deubzer; Dennis Wegener; Diana Pickert; Jan-Peter Linke; Barbara Hero; Annette Kopp-Schneider; Frank Westermann; Scott M. Ulrich; Andreas von Deimling; Matthias Fischer; Olaf Witt

50

HDAC8 substrates: Histones and beyond.  

PubMed

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 nonhistone 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. © 2012 Wiley Periodicals, Inc. Biopolymers 99: 112-126, 2013. PMID:23175386

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

2013-02-01

51

Computational Studies on the Histone Deacetylases and the Design of Selective Histone Deacetylase Inhibitors  

PubMed Central

The catalytic activity of the histone deacetylase (HDAC) enzymes is directly relevant to the pathogenesis of cancer as well as several other diseases. HDAC inhibitors have been shown to have the potential to treat several types of cancers. The role of computational study of the HDAC enzymes is reviewed, with particular emphasis on the important role of molecular modeling to the development of HDAC inhibitors with improved efficacy and selectivity. The use of two computational approaches—one structure-based, and the second ligand-based—toward inhibitors against the different HDAC sub-classes, are summarized. PMID:19355989

Wang, Difei

2009-01-01

52

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

53

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

PubMed Central

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

2014-01-01

54

Arabidopsis thaliana histone deacetylase 1 (AtHD1) and epigenetic regulation  

E-print Network

machinery and thus affect transcription activity of the gene. A key event in this process is reversible modification of core histones, which is catalyzed by histone acetyltransferases (HATs) and histone deacetylases (HDs, HDAs, or HDACs). In general...

Tian, Lu

2004-09-30

55

Regulation of Muscle Gene Expression by Histone Deacetylases  

Microsoft Academic Search

Histone deacetylases (HDACs) repress gene expression by deacetylating lysine residues in core histones, which promotes chromatin\\u000a condensation and thereby limits access of basal transcriptional machinery to gene regulatory elements. In the past 5 years,\\u000a HDACs have emerged as key regulators of gene expression in muscle. In this chapter, we discuss the initial findings linking\\u000a HDACs to the control of striated

Timothy A. McKinsey; Eric N. Olson

56

Dendritic cell development requires histone deacetylase activity  

PubMed Central

DCs develop from multipotent progenitors (MPPs), which commit into DC-restricted common dendritic cell progenitors (CDPs). CDPs further differentiate into classical DCs (cDCs) and plasmacytoid DCs (pDCs). Here, we studied the impact of histone acetylation on DC development in C57BL/6 mice by interfering with histone acetylation and deacetylation, employing histone deacetylase (HDAC) inhibitors. We observed that commitment of MPPs into CDPs was attenuated by HDAC inhibition and that pDC development was specifically blocked. Gene expression profiling revealed that HDAC inhibition prevents establishment of a DC-specific gene expression repertoire. Importantly, protein levels of the core DC transcription factor PU.1 were reduced in HDAC inhibitor-treated cells and consequently PU.1 recruitment at PU.1 target genes Fms-like tyrosine kinase 3 (Flt3), interferon regulatory factor 8 (IRF8), and PU.1 itself was impaired. Thus, our results demonstrate that attenuation of PU.1 expression by HDAC inhibition causes reduced expression of key DC regulators, which results in attenuation of DC development. We propose that chromatin modifiers, such as HDACs, are required for establishing a DC gene network, where Flt3/STAT3 signaling drives PU.1 and IRF8 expression and DC development. Taken together, our study identifies HDACs as critical regulators of DC lineage commitment and development. PMID:24810486

Chauvistré, Heike; Küstermann, Caroline; Rehage, Nina; Klisch, Theresa; Mitzka, Saskia; Felker, Piritta; Rose-John, Stefan; Zenke, Martin; Seré, Kristin M

2014-01-01

57

Tau--an inhibitor of deacetylase HDAC6 function.  

PubMed

Analysis of brain microtubule protein from patients with Alzheimer's disease showed decreased alpha tubulin levels along with increased acetylation of the alpha tubulin subunit, mainly in those microtubules from neurons containing neurofibrillary tau pathology. To determine the relationship of tau protein and increased tubulin acetylation, we studied the effect of tau on the acetylation-deacetylation of tubulin. Our results indicate that tau binds to the tubulin-deacetylase, histone deacetylase 6 (HDAC6), decreasing its activity with a consequent increase in tubulin acetylation. As expected, increased acetylation was also found in tubulin from wild-type mice compared with tubulin from mice lacking tau because of the tau-mediated inhibition of the deacetylase. In addition, we found that an excess of tau protein, as a HDAC6 inhibitor, prevents induction of autophagy by inhibiting proteasome function. PMID:19457097

Perez, Mar; Santa-Maria, Ismael; Gomez de Barreda, Elena; Zhu, Xiongwei; Cuadros, Raquel; Cabrero, Jose Roman; Sanchez-Madrid, Francisco; Dawson, Hana N; Vitek, Michael P; Perry, George; Smith, Mark A; Avila, Jesus

2009-06-01

58

Mice Lacking Histone Deacetylase 6 Have Hyperacetylated Tubulin but Are Viable and Develop Normally  

Microsoft Academic Search

Posttranslational modifications play important roles in regulating protein structure and function. Histone deacetylase 6 (HDAC6) is a mostly cytoplasmic class II HDAC, which has a unique structure with two catalytic domains and a domain binding ubiquitin with high affinity. This enzyme was recently identified as a multi- substrate protein deacetylase that can act on acetylated histone tails, -tubulin and Hsp90.

Yu Zhang; SoHee Kwon; Teppei Yamaguchi; Fabien Cubizolles; Sophie Rousseaux; Michaela Kneissel; Chun Cao; Na Li; Hwei-Ling Cheng; Katrin Chua; David Lombard; Adam Mizeracki; Gabriele Matthias; Frederick W. Alt; Saadi Khochbin; Patrick Matthias

2008-01-01

59

HDACs, histone deacetylation and gene transcription: from molecular biology to cancer therapeutics  

Microsoft Academic Search

Histone deacetylases (HDACs) and histone acetyl transferases (HATs) are two counteracting enzyme families whose enzymatic activity controls the acetylation state of protein lysine residues, notably those contained in the N-terminal extensions of the core histones. Acetylation of histones affects gene expression through its influence on chromatin conformation. In addition, several non-histone proteins are regulated in their stability or biological function

Paola Gallinari; Stefania Di Marco; Phillip Jones; Michele Pallaoro; Christian Steinkühler

2007-01-01

60

Histone deacetylase 3 regulates cyclin A stability.  

PubMed

PCAF and GCN5 acetylate cyclin A at specific lysine residues targeting it for degradation at mitosis. We report here that histone deacetylase 3 (HDAC3) directly interacts with and deacetylates cyclin A. HDAC3 interacts with a domain included in the first 171 aa of cyclin A, a region involved in the regulation of its stability. In cells, overexpression of HDAC3 reduced cyclin A acetylation whereas the knocking down of HDAC3 increased its acetylation. Moreover, reduction of HDAC3 levels induced a decrease of cyclin A that can be reversed by proteasome inhibitors. These results indicate that HDAC3 is able to regulate cyclin A degradation during mitosis via proteasome. Interestingly, HDAC3 is abruptly degraded at mitosis also via proteasome thus facilitating cyclin A acetylation by PCAF/GCN5, which will target cyclin A for degradation. Because cyclin A is crucial for S phase progression and mitosis entry, the knock down of HDAC3 affects cell cycle progression specifically at both, S phase and G2/M transition. In summary we propose here that HDAC3 regulates cyclin A stability by counteracting the action of the acetylases PCAF/GCN5. PMID:23760262

Vidal-Laliena, Miriam; Gallastegui, Edurne; Mateo, Francesca; Martínez-Balbás, Marian; Pujol, Maria Jesús; Bachs, Oriol

2013-07-19

61

Metabolism-related liabilities of a potent histone deacetylase (HDAC) inhibitor and relevance of the route of administration on its metabolic fate.  

PubMed

Compound A [1-methyl-N-{(1S)-1-[5-(2-naphthyl)-1H-imidazol-2-yl]-7-oxooctyl}piperidine-4-carboxamide is a potent class I histone deacetylase (HDAC) inhibitor that demonstrated good antiproliferative activity against human tumour cell lines of different origin. This compound showed high in vivo clearance in rats (160 ml min(-1) kg(-1)) due to metabolism. The main metabolite detected in urine after intravenous dosing was characterized as a dihydrohydroxy S-mercapturic acid conjugate. Following oral dosing, however, the mercapturic acid derivative was no longer the main metabolite but the major metabolites were mono- and di-glucuronide conjugates of oxidized species having a mass shift of +34 m/z with respect to the parent. Comparison of plasma concentration after intra-arterial infusion and intravenous infusion and incubation with microsomes from different tissues (liver, kidney, small intestine and lung) in the presence of beta-nicotinamide adenine dinucleotide phosphate (NADPH) indicated that the compound was highly cleared by the lung. Oxidation of the naphthalene moiety was demonstrated to be the cause of the high in vivo clearance of compound A and the potential for bioactivation of this group was flagged. PMID:19569735

Fonsi, M; Fiore, F; Jones, P; Kinzel, O; Laufer, R; Rowley, M; Monteagudo, E

2009-10-01

62

Interplay between histone deacetylases and autophagy - from cancer therapy to neurodegeneration  

Microsoft Academic Search

Histone deacetylases (HDACs) are chromatin modifiers that alter gene expression but also exert a broad range of functions outside the nucleus by deacetylating non-histone target proteins. They gained growing attention for their implications in disease treatment, mainly through research using HDAC-inhibiting compounds. Understanding the effects of HDAC function and deregulation has therefore become an important focus for both basic and

Oliver Trüe; Patrick Matthias

2012-01-01

63

Histone-deacetylase inhibitors: novel drugs for the treatment of cancer  

Microsoft Academic Search

The opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs) allow gene expression to be exquisitely regulated through chromatin remodelling. Aberrant transcription due to altered expression or mutation of genes that encode HATs, HDACs or their binding partners, is a key event in the onset and progression of cancer. HDAC inhibitors can reactivate gene expression and inhibit the growth

Ricky W. Johnstone

2002-01-01

64

Cancer biology: mechanism of antitumour action of vorinostat (suberoylanilide hydroxamic acid), a novel histone deacetylase inhibitor  

Microsoft Academic Search

Histone deacetylase (HDAC) inhibitors represent a potential new class of antitumor agents. Vorinostat (suberoylanilide hydroxamic acid or SAHA) is a potent inhibitor of HDAC activity and has undergone initial evaluation in several Phase I and II clinical trials. HDACs are enzymes that catalyse the removal of the acetyl moiety from the lysine residues of proteins, including the core nucleosomal histones.

V M Richon

2006-01-01

65

Optimization of a series of potent and selective ketone histone deacetylase inhibitors.  

PubMed

Histone deacetylase (HDAC) inhibitors offer a promising strategy for cancer therapy and the first generation HDAC inhibitors are currently in the clinic. Herein we describe the optimization of a series of ketone small molecule HDAC inhibitors leading to potent and selective class I HDAC inhibitors with good dog PK. PMID:18809328

Pescatore, Giovanna; Kinzel, Olaf; Attenni, Barbara; Cecchetti, Ottavia; Fiore, Fabrizio; Fonsi, Massimiliano; Rowley, Michael; Schultz-Fademrecht, Carsten; Serafini, Sergio; Steinkühler, Christian; Jones, Philip

2008-10-15

66

Optimization of a series of potent and selective ketone histone deacetylase inhibitors  

Microsoft Academic Search

Histone deacetylase (HDAC) inhibitors offer a promising strategy for cancer therapy and the first generation HDAC inhibitors are currently in the clinic. Herein we describe the optimization of a series of ketone small molecule HDAC inhibitors leading to potent and selective class I HDAC inhibitors with good dog PK.

Giovanna Pescatore; Olaf Kinzel; Barbara Attenni; Ottavia Cecchetti; Fabrizio Fiore; Massimiliano Fonsi; Michael Rowley; Carsten Schultz-Fademrecht; Sergio Serafini; Christian Steinkühler; Philip Jones

2008-01-01

67

Drug Insight: histone deacetylase inhibitor-based therapies for cutaneous T-cell lymphomas  

Microsoft Academic Search

Reversible acetylation is mediated by histone deacetylase (HDAC), which is involved in regulating a broad repertoire of physiological processes, many of which are under aberrant control in tumor cells. Inhibition of HDAC activity prompts tumor cells to enter apoptosis; therefore, the utility of HDAC inhibitors for the treatment of cancer has been investigated and several HDAC inhibitors have now entered

Omar Khan; Nicholas B La Thangue

2008-01-01

68

Histone deacetylases and mechanisms of regulation of gene expression.  

PubMed

In recent years it has become widely recognized that histone modification plays a pivotal role in controlling gene expression and is involved in a wide spectrum of disease regulation. Histone acetylation is a major modification that affects gene transcription and is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HATs acetylate lysines of histone proteins, resulting in the relaxation of chromatin structure, and they also facilitate gene activation. Conversely, HDACs remove acetyl groups from hyperacetylated histones and suppress general gene transcription. In addition to histones, numerous nonhistone proteins can be acetylated and deacetylated, and they also are involved in the regulation of a wide range of diseases. To date there are 18 HDACs in mammals classified into 4 classes based on homology to yeast HDACs. Accumulating evidence has revealed that HDACs play crucial roles in a variety of biological processes including inflammation, cell proliferation, apoptosis, and carcinogenesis. In this review we summarize the current state of knowledge of HDACs in carcinogenesis and describe the involvement of HDACs in cancer-associated molecular processes. It is hoped than an understanding of the role of HDACs in cancer will lead to the design of more potent and specific drugs targeting selective HDAC proteins for the treatment of the disease. PMID:25746103

Chen, Hong Ping; Zhao, Yu Tina; Zhao, Ting C

2015-01-01

69

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

70

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

71

Histone Deacetylase 6 Regulates Growth Factor-Induced Actin Remodeling and Endocytosis  

Microsoft Academic Search

Histone deacetylase 6 (HDAC6) is a cytoplasmic deacetylase that uniquely catalyzes -tubulin deacetylation and promotes cell motility. However, the mechanism underlying HDAC6-dependent cell migration and the role for microtubule acetylation in motility are not known. Here we show that HDAC6-induced global microtubule deacetylation was not sufficient to stimulate cell migration. Unexpectedly, in response to growth factor stimulation, HDAC6 underwent rapid

Ya-sheng Gao; Charlotte C. Hubbert; Jianrong Lu; Yi-Shan Lee; Joo-Yong Lee; Tso-Pang Yao

2007-01-01

72

Epigenetics in sepsis: targeting histone deacetylases.  

PubMed

Severe sepsis and septic shock are lethal complications of infection, characterised by dysregulated inflammatory and immune responses. Our understanding of the pathogenesis of sepsis has improved markedly in recent years, but unfortunately has not been translated into efficient treatment strategies. Epigenetic mechanisms such as covalent modification of histones by acetylation are master regulators of gene expression under physiological and pathological conditions, and strongly impact on inflammatory and host defence responses. Histone acetylation is controlled by histone acetyltransferases and histone deacetylases (HDACs), which affect gene expression also by targeting non-histone transcriptional regulators. Numerous HDAC inhibitors (HDACi) are being tested in clinical trials, primarily for the treatment of cancer. We performed the first comprehensive study of the impact of HDACi on innate immune responses in vitro and in vivo. We showed that HDACi act essentially as negative regulators of the expression of critical immune receptors and antimicrobial pathways in innate immune cells. In agreement, HDACi impaired phagocytosis and killing of bacteria by macrophages, and increased susceptibility to non-severe bacterial and fungal infections. Strikingly, proof-of-principle studies demonstrated that HDACi protect from lethal toxic shock and septic shock. Overall, our observations argue for a close monitoring of the immunological and infection status of patients treated with HDACi, especially immunocompromised cancer patients. They also support the concept of pharmacological inhibitors of HDACs as promising drugs to treat inflammatory diseases, including sepsis. PMID:23664675

Ciarlo, Eleonora; Savva, Athina; Roger, Thierry

2013-06-01

73

Histone Deacetylase Inhibitors through Click Chemistry  

PubMed Central

Histone deacetylase inhibitors (HDACi) are a relatively new class of chemotherapy agents. Herein, we report a click-chemistry based approach to the synthesis of HDACi. Fourteen agents were synthesized from the combination of two alkyne and seven azido precursors. The inhibition of HDAC1 and HDAC8 was then determined by in vitro enzymatic assays, after which the cytotoxicity was evaluated in the NCI human cancer cell line screen. A lead compound 5g (NSC746457) was discovered that inhibited HDAC1 at an IC50 value of 104 ± 30 nM and proved quite potent in the cancer cell line screen with GI50 values ranging from 3.92 ?M to 10 nM. Thus, this click HDACi design has provided a new chemical scaffold that has not only revealed a lead compound, but one which is easily amendable to further structural modifications given the modular nature of this approach. PMID:19007204

Shen, Jie; Woodward, Robert; Kedenburg, James Patrick; Liu, Xianwei; Chen, Min; Fang, Lanyan; Sun, Duxin; Wang, Peng George

2012-01-01

74

[DNA methyltransferase inhibitors * histone deacetylase inhibitors].  

PubMed

Epigenetics is a cell intrinsic mechanism to maintain genomic integrity by modifying chromatin architecture independently of changes in heritable DNA sequences namely genetic code. Chromatin is composed of nucleosome cores, in which DNA(147bp) is wrapped around a core histone octamer(two each of histones H2A, H2B, H3 and H4), arranged in a "beads-on-a-string array" with linker histones and non-histone nuclear proteins. The chromatin structure could be altered by chemical modifications of DNA and histones, including methylation and acetylation, without affecting genetic codes. In mammals, DNA methylation is mediated via DNA methyltransferases (Dnmt) at CpG dinucleotides. Histones are modified by numerous enzymes, such as histone acetyltransferases (HATs), deacetylases (HDACs), methyltransferases and demethylases, in spatio-temporarily distinct manners. These modifications could alter chromatin structures to regulate a wide variety of biological processes such as gene expression, cell cycle progression and DNA repair. Given the biological importance of epigenetic modifications, it is easy to speculate that the abnormalities of chromatin modifying enzymes and reader proteins underlie several human diseases such as cancer, inflammation and metabolic disorders. Because epigenetic states are reversible and could be modified in response to extrinsic signals, including small molecular compounds, an increased understanding of their molecular framework would allow us to treat pathological conditions caused by epigenetic alterations. Indeed, Dnmt inhibitors and HDAC inhibitors have already applied to the treatment of hematological malignancies with considerable success. PMID:25016817

Kikuchi, Jiro; Furukawa, Yusuke

2014-06-01

75

Histone deacetylases in cardiac fibrosis: current perspectives for therapy.  

PubMed

Cardiac fibrosis is an important pathological feature of cardiac remodeling in heart diseases. The molecular mechanisms of cardiac fibrosis are unknown. Histone deacetylases (HDACs) are enzymes that balance the acetylation activities of histone acetyltransferases on chromatin remodeling and play essential roles in regulating gene transcription. In recent years, the role of HDACs in cardiac fibrosis initiation and progression, as well as the therapeutic effects of HDAC inhibitors, has been well studied. Moreover, numerous studies indicated that HDAC activity is associated with the development and progression of cardiac fibrosis. In this review, the innovative aspects of HDACs are discussed, with respect to biogenesis, their role in cardiac fibrosis. Furthermore, the potential applications of HDAC inhibitors in the treatment of cardiac fibrosis associated with fibroblast activation and proliferation. PMID:24321371

Tao, Hui; Shi, Kai-Hu; Yang, Jing-Jing; Huang, Cheng; Zhan, Hong-Ying; Li, Jun

2014-03-01

76

Histone deacetylase inhibition as an alternative strategy against invasive aspergillosis  

PubMed Central

Invasive aspergillosis (IA) is a life-threatening infection due to Aspergillus fumigatus and other Aspergillus spp. Drugs targeting the fungal cell membrane (triazoles, amphotericin B) or cell wall (echinocandins) are currently the sole therapeutic options against IA. Their limited efficacy and the emergence of resistance warrant the identification of new antifungal targets. Histone deacetylases (HDACs) are enzymes responsible of the deacetylation of lysine residues of core histones, thus controlling chromatin remodeling and transcriptional activation. HDACs also control the acetylation and activation status of multiple non-histone proteins, including the heat shock protein 90 (Hsp90), an essential molecular chaperone for fungal virulence and antifungal resistance. This review provides an overview of the different HDACs in Aspergillus spp. as well as their respective contribution to total HDAC activity, fungal growth, stress responses, and virulence. The potential of HDAC inhibitors, currently under development for cancer therapy, as novel alternative antifungal agents against IA is discussed.

Lamoth, Frédéric; Juvvadi, Praveen R.; Steinbach, William J.

2015-01-01

77

Histone deacetylase inhibition as an alternative strategy against invasive aspergillosis.  

PubMed

Invasive aspergillosis (IA) is a life-threatening infection due to Aspergillus fumigatus and other Aspergillus spp. Drugs targeting the fungal cell membrane (triazoles, amphotericin B) or cell wall (echinocandins) are currently the sole therapeutic options against IA. Their limited efficacy and the emergence of resistance warrant the identification of new antifungal targets. Histone deacetylases (HDACs) are enzymes responsible of the deacetylation of lysine residues of core histones, thus controlling chromatin remodeling and transcriptional activation. HDACs also control the acetylation and activation status of multiple non-histone proteins, including the heat shock protein 90 (Hsp90), an essential molecular chaperone for fungal virulence and antifungal resistance. This review provides an overview of the different HDACs in Aspergillus spp. as well as their respective contribution to total HDAC activity, fungal growth, stress responses, and virulence. The potential of HDAC inhibitors, currently under development for cancer therapy, as novel alternative antifungal agents against IA is discussed. PMID:25762988

Lamoth, Frédéric; Juvvadi, Praveen R; Steinbach, William J

2015-01-01

78

Histone Deacetylase Inhibitors: A Novel Therapeutic Approach for Cognitive Disorders  

Microsoft Academic Search

\\u000a Epigenetic mechanisms have a central role in regulating gene expression and are capable of influencing complex cognitive functions.\\u000a In particular, acetylation of histone proteins is an epigenetic modification involved in mediating synaptic plasticity, learning,\\u000a and memory. Emerging evidence indicates that increased histone acetylation through the inhibition of histone deacetylases\\u000a (HDACs) can facilitate the formation of long-term memories in preclinical studies.

Viviane Labrie

79

A combined approach for the study of histone deacetylase inhibitors.  

PubMed

Overexpression of histone deacetylases (HDACs), with consequent hypoacetylation of histones, is reportedly associated with transcriptional repression of tumour suppressor genes. Thus, inhibition of HDACs has emerged as a promising strategy in cancer therapy. In order to monitor the effects of potential HDAC inhibitors, a multi-level approach consisting of preliminary screening (measurement of HDAC activity and semi-quantitative evaluation of histone H4 modification profile by MALDI-TOF MS) and detailed analysis of histone modification forms (using 2-D AUT/AU PAGE and LC-ESI-IT MS) has been used in this study. The data obtained provide a global insight into the effects of HDAC inhibitors on the histone acetylation status that participates in gene transcription control. Using two example inhibitors, valproic acid sodium salt and entinostat, we show that similar levels of HDAC inhibition induced by different agents can lead to distinct rates of histone hyperacetylation, suggesting that except for the direct inhibition of HDACs, additional molecular mechanisms amplifying the response are likely to be involved in the inhibitory process. The approach used in our study makes it possible not only to follow the dynamics of individual histone modification forms, but also of their combined occurrence in the N-terminal fragment. PMID:22915142

?in?árová, Lenka; Lochmanová, Gabriela; Nováková, Kate?ina; Šultesová, Pavla; Kone?ná, Hana; Fajkusová, Lenka; Fajkus, Ji?í; Zdráhal, Zbyn?k

2012-11-01

80

The many roles of histone deacetylases in development and physiology: implications for disease and therapy  

Microsoft Academic Search

Histone deacetylases (HDACs) are part of a vast family of enzymes that have crucial roles in numerous biological processes, largely through their repressive influence on transcription. The expression of many HDAC isoforms in eukaryotic cells raises questions about their possible specificity or redundancy, and whether they control global or specific programmes of gene expression. Recent analyses of HDAC knockout mice

Michael Haberland; Rusty L. Montgomery; Eric N. Olson

2009-01-01

81

Novel Inhibitor of Plasmodium Histone Deacetylase That Cures P. berghei-Infected Mice  

Microsoft Academic Search

Histone deacetylases (HDAC) are potential targets for the development of new antimalarial drugs. The growth of Plasmodium falciparum and other apicomplexans can be suppressed in the presence of potent HDAC inhibitors in vitro and in vivo; however, in vivo parasite suppression is generally incomplete or reversible after the discontinuation of drug treatment. Furthermore, most established HDAC inhibitors concurrently show broad

S. Agbor-Enoh; C. Seudieu; E. Davidson; A. Dritschilo; M. Jung

2009-01-01

82

Developmental Expression of Histone Deacetylase 11 in the Murine Brain  

PubMed Central

Recent studies indicate that neural cell development in the central nervous system (CNS) correlates with a reduction in acetylation of histone core proteins. Moreover, histone hypoacetylation is thought to be important to oligodendrocyte lineage development. The mechanisms mediating the reduction in acetylation during postnatal neural development remain to be defined. To begin to understand these mechanisms, we investigated the expression of histone deacetylase 11 (HDAC11), a newly identified HDAC, in mouse brain during postnatal development. We show that HDAC11 was widely expressed in the brain and that this expression gradually increased in a region-specific pattern between birth and 4 weeks of age. At the cellular level HDAC11 protein was predominately localized in the nuclei of mature oligodendrocytes but only minimally in astrocytes. Although dentate gyrus granule neurons abundantly expressed HDAC11, granule neuron precursors in the subgranule layer exhibited little HDAC11 immunoreactivity. Double-immunostaining of the corpus callosum and dentate gyrus demonstrated that HDAC11 and Ki67, a cell-proliferating marker, are rarely colocalized in same cells. Our data show that HDAC11 was expressed in the developing brain in a temporal and spatial pattern that correlates with the maturation of neural cells, including cells of the oligodendrocyte lineage. These findings support a role for HDAC11 in CNS histone deacetylation and the development of oligodendrocytes and neurons during postnatal development. PMID:17893925

Liu, Hedi; Hu, Qichen; Kaufman, Amanda; D’Ercole, A. Joseph; Ye, Ping

2008-01-01

83

Antimalarial histone deacetylase inhibitors containing cinnamate or NSAID components  

Microsoft Academic Search

Malaria is the most lethal parasite-mediated tropical infectious disease, killing 1–2 million people each year. An emerging drug target is the enzyme Plasmodium falciparum histone deacetylase 1 (PfHDAC1). We report 26 compounds designed to bind the zinc and exterior surface around the entrance to the active site of PfHDAC1, 16 displaying potent in vitro antimalarial activity (IC50<100nM) against P. falciparum.

Nicole C. Wheatley; Katherine T. Andrews; Truc L. Tran; Andrew J. Lucke; Robert C. Reid; David P. Fairlie

2010-01-01

84

Therapeutic application of histone deacetylase inhibitors for central nervous system disorders  

Microsoft Academic Search

Histone deacetylases (HDACs) — enzymes that affect the acetylation status of histones and other important cellular proteins — have been recognized as potentially useful therapeutic targets for a broad range of human disorders. Pharmacological manipulations using small-molecule HDAC inhibitors — which may restore transcriptional balance to neurons, modulate cytoskeletal function, affect immune responses and enhance protein degradation pathways — have

Leslie M. Thompson; Aleksey G. Kazantsev

2008-01-01

85

Targeting histone deacetylases in pancreatic ductal adenocarcinoma  

PubMed Central

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with a median survival below 6 months and a 5-year survival rate below 1%. Effective therapies for locally advanced or metastatic tumours are missing and curatively resected patients relapse in over 80% of the cases. Although histone deacetylases (HDACs) are involved in the control of proliferation, apoptosis, differentiation, migration and angiogenesis of cancer cells, knowledge about the expression patterns and functions of individual HDAC isoenzymes in pancreatic cancer is sparse. This review summarizes the roles of HDACs as novel therapeutic targets and the molecular mode of action of HDAC-inhibitors (HDACI) in PDACs. Success of HDACI in clinical settings will depend on an increased knowledge of HDAC functions as well as on a better understanding of the mode of action of HDACI. Pre-clinical experimental data that constitute the basis for rational therapeutic strategies to treat PDAC are described here. Translating these rational-based therapies into the clinic will finally increase our chance to establish an effective HDACI-containing combination therapy effective against PDAC. PMID:19929947

Schneider, Günter; Krämer, Oliver H; Fritsche, Petra; Schüler, Susanne; Schmid, Roland M; Saur, Dieter

2010-01-01

86

Isoform-specific histone deacetylase inhibitors: The next step?  

Microsoft Academic Search

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

Sriram Balasubramanian; Erik Verner; Joseph J. Buggy

2009-01-01

87

Histone deacetylase 9 is a negative regulator of adipogenic differentiation.  

PubMed

Differentiation of preadipocytes into mature adipocytes capable of efficiently storing lipids is an important regulatory mechanism in obesity. Here, we examined the involvement of histone deacetylases (HDACs) and histone acetyltransferases (HATs) in the regulation of adipogenesis. We find that among the various members of the HDAC and HAT families, only HDAC9 exhibited dramatic down-regulation preceding adipogenic differentiation. Preadipocytes from HDAC9 gene knock-out mice exhibited accelerated adipogenic differentiation, whereas HDAC9 overexpression in 3T3-L1 preadipocytes suppressed adipogenic differentiation, demonstrating its direct role as a negative regulator of adipogenesis. HDAC9 expression was higher in visceral as compared with subcutaneous preadipocytes, negatively correlating with their potential to undergo adipogenic differentiation in vitro. HDAC9 localized in the nucleus, and its negative regulation of adipogenesis segregates with the N-terminal nuclear targeting domain, whereas the C-terminal deacetylase domain is dispensable for this function. HDAC9 co-precipitates with USF1 and is recruited with USF1 at the E-box region of the C/EBP? gene promoter in preadipocytes. Upon induction of adipogenic differentiation, HDAC9 is down-regulated, leading to its dissociation from the USF1 complex, whereas p300 HAT is up-regulated to allow its association with USF1 and accumulation at the E-box site of the C/EBP? promoter in differentiated adipocytes. This reciprocal regulation of HDAC9 and p300 HAT in the USF1 complex is associated with increased C/EBP? expression, a master regulator of adipogenic differentiation. These findings provide new insights into mechanisms of adipogenic differentiation and document a critical regulatory role for HDAC9 in adipogenic differentiation through a deacetylase-independent mechanism. PMID:21680747

Chatterjee, Tapan K; Idelman, Gila; Blanco, Victor; Blomkalns, Andra L; Piegore, Mark G; Weintraub, Daniel S; Kumar, Santosh; Rajsheker, Srinivas; Manka, David; Rudich, Steven M; Tang, Yaoliang; Hui, David Y; Bassel-Duby, Rhonda; Olson, Eric N; Lingrel, Jerry B; Ho, Shuk-Mei; Weintraub, Neal L

2011-08-01

88

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

89

Association of Class II Histone Deacetylases with Heterochromatin Protein 1: Potential Role for Histone Methylation in Control of Muscle Differentiation  

Microsoft Academic Search

Class II histone deacetylases (HDACs) 4, 5, 7, and 9 repress muscle differentiation through associations with the myocyte enhancer factor 2 (MEF2) transcription factor. MEF2-interacting transcription repressor (MITR) is an amino-terminal splice variant of HDAC9 that also potently inhibits MEF2 transcriptional activity despite lacking a catalytic domain. Here we report that MITR, HDAC4, and HDAC5 associate with heterochromatin protein 1

Chun Li Zhang; Timothy A. McKinsey; Eric N. Olson

2002-01-01

90

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

91

Regulation of Tat acetylation and transactivation activity by the microtubule-associated deacetylase HDAC6.  

PubMed

Reversible acetylation of Tat is critical for its transactivation activity toward HIV-1 transcription. However, the enzymes involved in the acetylation/deacetylation cycles have not been fully characterized. In this study, by yeast two-hybrid assay, we have discovered the histone deacetylase HDAC6 to be a binding partner of Tat. Our data show that HDAC6 interacts with Tat in the cytoplasm in a microtubule-dependent manner. In addition, HDAC6 deacetylates Tat at Lys-28 and thereby suppresses Tat-mediated transactivation of the HIV-1 promoter. Inactivation of HDAC6 promotes the interaction of Tat with cyclin T1 and leads to an increase in Tat transactivation activity. These findings establish HDAC6 as a Tat deacetylase and support a model in which Lys-28 deacetylation decreases Tat transactivation activity through affecting the ability of Tat to form a ribonucleoprotein complex with cyclin T1 and the transactivation-responsive RNA. PMID:21220424

Huo, Lihong; Li, Dengwen; Sun, Xiaoou; Shi, Xingjuan; Karna, Prasanthi; Yang, Wei; Liu, Min; Qiao, Wentao; Aneja, Ritu; Zhou, Jun

2011-03-18

92

Drug Insight: histone deacetylase inhibitors—development of the new targeted anticancer agent suberoylanilide hydroxamic acid  

Microsoft Academic Search

This review focuses on the discovery and development of the histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA). Post-translational modifications of the histones of chromatin are important factors in regulating gene expression—so-called epigenetic gene regulation. Acetylation and deacetylation of lysine residues in histone tails, controlled by the activities of HDACs and histone acetyltransferases, are among the most studied post-translational modification

William Kevin Kelly; Paul A Marks

2005-01-01

93

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

94

Identification of Histone Deacetylase Inhibitors with Benzoylhydrazide Scaffold that Selectively Inhibit Class I Histone Deacetylases.  

PubMed

Inhibitors of histone deacetylases (HDACi) hold considerable therapeutic promise as clinical anticancer therapies. However, currently known HDACi exhibit limited isoform specificity, off-target activity, and undesirable pharmaceutical properties. Thus, HDACi with new chemotypes are needed to overcome these limitations. Here, we identify a class of HDACi with a previously undescribed benzoylhydrazide scaffold that is selective for the class I HDACs. These compounds are competitive inhibitors with a fast-on/slow-off HDAC-binding mechanism. We show that the lead compound, UF010, inhibits cancer cell proliferation via class I HDAC inhibition. This causes global changes in protein acetylation and gene expression, resulting in activation of tumor suppressor pathways and concurrent inhibition of several oncogenic pathways. The isotype selectivity coupled with interesting biological activities in suppressing tumor cell proliferation support further preclinical development of the UF010 class of compounds for potential therapeutic applications. PMID:25699604

Wang, Yunfei; Stowe, Ryan L; Pinello, Christie E; Tian, Guimei; Madoux, Franck; Li, Dawei; Zhao, Lisa Y; Li, Jian-Liang; Wang, Yuren; Wang, Yuan; Ma, Haiching; Hodder, Peter; Roush, William R; Liao, Daiqing

2015-02-19

95

Loss of Epigenetic Kruppel-like Factor 4 Histone Deacetylase (KLF-4-HDAC)-mediated Transcriptional Suppression Is Crucial in Increasing Vascular Endothelial Growth Factor (VEGF) Expression in Breast Cancer*  

PubMed Central

Vascular endothelial growth factor (VEGF) is recognized as an important angiogenic factor that promotes angiogenesis in a series of pathological conditions, including cancer, inflammation, and ischemic disorders. We have recently shown that the inflammatory transcription factor SAF-1 is, at least in part, responsible for the marked increase of VEGF levels in breast cancer. Here, we show that SAF-1-mediated induction of VEGF is repressed by KLF-4 transcription factor. KLF-4 is abundantly present in normal breast epithelial cells, but its level is considerably reduced in breast cancer cells and clinical cancer tissues. In the human VEGF promoter, SAF-1- and KLF-4-binding elements are overlapping, whereas SAF-1 induces and KLF-4 suppresses VEGF expression. Ectopic overexpression of KLF-4 and RNAi-mediated inhibition of endogenous KLF-4 supported the role of KLF-4 as a transcriptional repressor of VEGF and an inhibitor of angiogenesis in breast cancer cells. We show that KLF-4 recruits histone deacetylases (HDACs) -2 and -3 at the VEGF promoter. Chronological ChIP assays demonstrated the occupancy of KLF-4, HDAC2, and HDAC3 in the VEGF promoter in normal MCF-10A cells but not in MDA-MB-231 cancer cells. Co-transfection of KLF-4 and HDAC expression plasmids in breast cancer cells results in synergistic repression of VEGF expression and inhibition of angiogenic potential of these carcinoma cells. Together these results identify a new mechanism of VEGF up-regulation in cancer that involves concomitant loss of KLF-4-HDAC-mediated transcriptional repression and active recruitment of SAF-1-mediated transcriptional activation. PMID:23926105

Ray, Alpana; Alalem, Mohamed; Ray, Bimal K.

2013-01-01

96

Differential effects of class I isoform histone deacetylase depletion and enzymatic inhibition by belinostat or valproic acid in HeLa cells  

Microsoft Academic Search

BACKGROUND: Histone acetylation is an epigenetic modification involved in the regulation of gene expression, balanced by histone acetyl transferases and histone deacetylase (HDAC) enzymes. HDAC inhibitors (HDACi) induce growth arrest and cell death in transformed cells, and are currently in many clinical cancer trials. The transcriptional response to HDACi is complex, as is the response to HDAC isoform knockdown (KD).

Marielle Dejligbjerg; Morten Grauslund; Thomas Litman; Laura Collins; Xiaozhong Qian; Michael Jeffers; Henri Lichenstein; Peter Buhl Jensen; Maxwell Sehested

2008-01-01

97

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

98

DNA Methyltransferase Inhibition Enhances Apoptosis Induced by Histone Deacetylase Inhibitors1  

Microsoft Academic Search

Histone acetylation has long been associated with transcriptional acti- vation, whereas conversely, deacetylation of histones is associated with gene silencing and transcriptional repression. Here we report that inhib- itors of histone deacetylase (HDAC), depsipeptide and trichostatin A, induce apoptotic cell death in human lung cancer cells as demonstrated by DNA flow cytometry and Western immunoblot to detect cleavage of poly(ADP-ribose)

Wei-Guo Zhu; Romola R. Lakshmanan; Matthew D. Beal; Gregory A. Otterson

2001-01-01

99

The functional interactome landscape of the human histone deacetylase family  

PubMed Central

Histone deacetylases (HDACs) are a diverse family of essential transcriptional regulatory enzymes, that function through the spatial and temporal recruitment of protein complexes. As the composition and regulation of HDAC complexes are only partially characterized, we built the first global protein interaction network for all 11 human HDACs in T cells. Integrating fluorescence microscopy, immunoaffinity purifications, quantitative mass spectrometry, and bioinformatics, we identified over 200 unreported interactions for both well-characterized and lesser-studied HDACs, a subset of which were validated by orthogonal approaches. We establish HDAC11 as a member of the survival of motor neuron complex and pinpoint a functional role in mRNA splicing. We designed a complementary label-free and metabolic-labeling mass spectrometry-based proteomics strategy for profiling interaction stability among different HDAC classes, revealing that HDAC1 interactions within chromatin-remodeling complexes are largely stable, while transcription factors preferentially exist in rapid equilibrium. Overall, this study represents a valuable resource for investigating HDAC functions in health and disease, encompassing emerging themes of HDAC regulation in cell cycle and RNA processing and a deeper functional understanding of HDAC complex stability. PMID:23752268

Joshi, Preeti; Greco, Todd M; Guise, Amanda J; Luo, Yang; Yu, Fang; Nesvizhskii, Alexey I; Cristea, Ileana M

2013-01-01

100

Intracellular translocation of histone deacetylase 5 regulates neuronal cell apoptosis.  

PubMed

Histone deacetylase 5 (HDAC5) undergoes signal-dependent shuttling between the nucleus and cytoplasm, which is regulated in part by calcium/calmodulin-dependent kinase (CaMK)-mediated phosphorylation. Here, we report that HDAC5 regulates the survival of cortical neurons in pathological conditions. HDAC5 was evenly localized to the nucleus and cytoplasm in cultured cortical neurons. However, in response to 50?M NMDA conditions that induced neuronal cell apoptosis, nuclear-distributed HDAC5 was rapidly phosphorylated and translocated into cytoplasm of the cultured cortical neurons. Treatment with a CaMKII inhibitor KN93 suppressed HDAC5 phosphorylation and nuclear translocation induced by NMDA, whereas constitutively active CaMKII? (T286D) stimulated HDAC5 nuclear export. Importantly, we showed that ectopic expression of nuclear-localized HDAC5 in cortical neurons suppressed NMDA-induced apoptosis. Finally, inactivation of HDAC5 by treatment with the class II-specific HDAC inhibitor trichostatin A (TSA) promoted NMDA-induced neuronal cell apoptosis. Altogether, these data identify HDAC5 and its intracellular translocation as key effectors of multiple pathways that regulate neuronal cell apoptosis. PMID:25661252

Wei, Jia-Yi; Lu, Qiu-Nan; Li, Wan-Ming; He, Wei

2015-04-16

101

Three proteins define a class of human histone deacetylases related to yeast Hda1p  

PubMed Central

Gene expression is in part controlled by chromatin remodeling factors and the acetylation state of nucleosomal histones. The latter process is regulated by histone acetyltransferases and histone deacetylases (HDACs). Previously, three human and five yeast HDAC enzymes had been identified. These can be categorized into two classes: the first class represented by yeast Rpd3-like proteins and the second by yeast Hda1-like proteins. Human HDAC1, HDAC2, and HDAC3 proteins are members of the first class, whereas no class II human HDAC proteins had been identified. The amino acid sequence of Hda1p was used to search the GenBank/expressed sequence tag databases to identify partial sequences from three putative class II human HDAC proteins. The corresponding full-length cDNAs were cloned and defined as HDAC4, HDAC5, and HDAC6. These proteins possess certain features present in the conserved catalytic domains of class I human HDACs, but also contain additional sequence domains. Interestingly, HDAC6 contains an internal duplication of two catalytic domains, which appear to function independently of each other. These class II HDAC proteins have differential mRNA expression in human tissues and possess in vitro HDAC activity that is inhibited by trichostatin A. Coimmunoprecipitation experiments indicate that these HDAC proteins are not components of the previously identified HDAC1 and HDAC2 NRD and mSin3A complexes. However, HDAC4 and HDAC5 associate with HDAC3 in vivo. This finding suggests that the human class II HDAC enzymes may function in cellular processes distinct from those of HDAC1 and HDAC2. PMID:10220385

Grozinger, Christina M.; Hassig, Christian A.; Schreiber, Stuart L.

1999-01-01

102

DNA methyltransferase Dnmt1 associates with histone deacetylase activity.  

PubMed

The DNA methyltransferase Dnmt1 is responsible for cytosine methylation in mammals and has a role in gene silencing. DNA methylation represses genes partly by recruitment of the methyl-CpG-binding protein MeCP2, which in turn recruits a histone deacetylase activity. Here we show that Dnmt1 is itself associated with histone deacetylase activity in vivo. Consistent with this association, we find that one of the known histone deacetylases, HDAC1, has the ability to bind Dnmt1 and can purify methyltransferase activity from nuclear extracts. We have identified a transcriptional repression domain in Dnmt1 that functions, at least partly, by recruiting histone deacetylase activity and shows homology to the repressor domain of the trithorax-related protein HRX (also known as MLL and ALL-1). Our data show a more direct connection between DNA methylation and histone deacetylation than was previously considered. We suggest that the process of DNA methylation, mediated by Dnmt1, may depend on or generate an altered chromatin state via histone deacetylase activity. PMID:10615135

Fuks, F; Burgers, W A; Brehm, A; Hughes-Davies, L; Kouzarides, T

2000-01-01

103

Histone deacetylase 1 and 2 regulate Wnt and p53 pathways in the ureteric bud epithelium.  

PubMed

Histone deacetylases (HDACs) regulate a broad range of biological processes through removal of acetyl groups from histones as well as non-histone proteins. Our previous studies showed that Hdac1 and Hdac2 are bound to promoters of key renal developmental regulators and that HDAC activity is required for embryonic kidney gene expression. However, the existence of many HDAC isoforms in embryonic kidneys raises questions concerning the possible specificity or redundancy of their functions. We report here that targeted deletion of both the Hdac1 and Hdac2 genes from the ureteric bud (UB) cell lineage of mice causes bilateral renal hypodysplasia. One copy of either Hdac1 or Hdac2 is sufficient to sustain normal renal development. In addition to defective cell proliferation and survival, genome-wide transcriptional profiling revealed that the canonical Wnt signaling pathway is specifically impaired in UB(Hdac1,2-/-) kidneys. Our results also demonstrate that loss of Hdac1 and Hdac2 in the UB epithelium leads to marked hyperacetylation of the tumor suppressor protein p53 on lysine 370, 379 and 383; these post-translational modifications are known to boost p53 stability and transcriptional activity. Genetic deletion of p53 partially rescues the development of UB(Hdac1,2-/-) kidneys. Together, these data indicate that Hdac1 and Hdac2 are crucial for kidney development. They perform redundant, yet essential, cell lineage-autonomous functions via p53-dependent and -independent pathways. PMID:25758227

Chen, Shaowei; Yao, Xiao; Li, Yuwen; Saifudeen, Zubaida; Bachvarov, Dimcho; El-Dahr, Samir S

2015-03-15

104

Estrogen regulates histone deacetylases to prevent cardiac hypertrophy  

PubMed Central

The development and progression of cardiac hypertrophy often leads to heart failure and death, and important modulators of hypertrophy include the histone deacetylase proteins (HDACs). Estrogen inhibits cardiac hypertrophy and progression in animal models and humans. We therefore investigated the influence of 17-?-estradiol on the production, localization, and functions of prohypertrophic (class I) and antihypertrophic (class II) HDACs in cultured neonatal rat cardiomyocytes. 17-?-Estradiol or estrogen receptor ? agonists dipropylnitrile and ?-LGND2 comparably suppressed angiotensin II–induced HDAC2 (class I) production, HDAC-activating phosphorylation, and the resulting prohypertrophic mRNA expression. In contrast, estrogenic compounds derepressed the opposite effects of angiotensin II on the same parameters for HDAC4 and 5 (class II), resulting in retention of these deacetylases in the nucleus to inhibit hypertrophic gene expression. Key aspects were confirmed in vivo from the hearts of wild-type but not estrogen receptor ? (ER?) gene–deleted mice administered angiotensin II and estrogenic compounds. Our results identify a novel dual regulation of cardiomyocyte HDACs, shown here for the antihypertrophic sex steroid acting at ER?. This mechanism potentially supports using ER? agonists as HDAC modulators to treat cardiac disease. PMID:24152730

Pedram, Ali; Razandi, Mahnaz; Narayanan, Ramesh; Dalton, James T.; McKinsey, Timothy A.; Levin, Ellis R.

2013-01-01

105

Current Opinion in Genetics and Development Volume 11, Issue 2, 1 April 2001, Pages 162-166 Functional significance of histone deacetylase diversity  

E-print Network

of HDACs in higher eukaryotes. The diversity of histone deacetylases has also been observed in plants is to evaluate how the diversity of HDACs could be linked to distinct functions in the animal kingdom. Functional-166 Functional significance of histone deacetylase diversity Saadi Khochbin* , André Verdel, Claudie Lemercier

Boyer, Edmond

106

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

107

A positive regulatory domain in CCAAT/enhancer binding protein ? (C/EBP?) is required for the glucocorticoid-mediated displacement of histone deacetylase 1 (HDAC1) from the C/ebp? promoter and maximum adipogenesis.  

PubMed

Glucocorticoids promote adipogenesis and contribute to the metabolic syndrome through a number of mechanisms. One of the effectors of glucocorticoid action is the CCAAT/enhancer binding protein ? (C/EBP?). C/EBP? is a basic leucine-zipper transcription factor involved in diverse processes including differentiation, cellular proliferation, and inflammation. C/EBP? transcriptional activity is regulated, in part, by its acetylation profile resulting from its dynamic interaction with either acetylases general control nonrepressed protein 5/p300/CBP associated factor (GCN5/PCAF) or deacetylase complexes (mSin3A/histone deacetylase 1 [HDAC1]). Glucocorticoid treatment of preadipocytes promotes C/EBP? acetylation, leading to mSin3A/HDAC1 dissociation from C/EBP? and resulting in C/ebp? promoter activation at the onset of adipogenesis, thus increasing the differentiation rate. We recently showed that the regulatory domain 1 (RD1) of C/EBP? contains four residues (153-156) required for its interaction with HDAC1, therefore supporting RD1 proposed inhibitory role. In an attempt to further elucidate the intrinsic regulatory property of RD1, we sought to characterize the regulatory potential of the N terminus region of RD1 (residues 141-149). In this study, we show that C/EBP??141-149 transcriptional activity was compromised on the C/ebp?, but not on the Ppar?, promoter. Additionally, the ability of C/EBP??141-149 to induce adipogenesis in NIH 3T3 cells was compromised when compared with C/EBP?wt owing to a delayed expression of C/ebp? at the onset of differentiation. Furthermore, the data suggest that the reduced expression of C/ebp? in cells expressing C/EBP??141-149 was due to a persistent recruitment of HDAC1 to the C/ebp? promoter after glucocorticoid treatment. Together, these results suggest that amino acids 141-149 of C/EBP? act as a positive regulatory domain required for maximum transcriptional activity. PMID:23456364

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

2013-04-01

108

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

109

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. PMID:25694842

Sharma, Sorabh; Taliyan, Rajeev

2015-01-01

110

Targeting histone deacetylases: a novel approach in Parkinson's disease.  

PubMed

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. PMID:25694842

Sharma, Sorabh; Taliyan, Rajeev

2015-01-01

111

Histone acetylation and histone deacetylase activity of magnesium valproate in tumor and peripheral blood of patients with cervical cancer. A phase I study  

Microsoft Academic Search

BACKGROUND: The development of cancer has been associated with epigenetic alterations such as aberrant histone deacetylase (HDAC) activity. It was recently reported that valproic acid is an effective inhibitor of histone deacetylases and as such induces tumor cell differentiation, apoptosis, or growth arrest. METHODS: Twelve newly diagnosed patients with cervical cancer were treated with magnesium valproate after a baseline tumor

Alma Chavez-Blanco; Blanca Segura-Pacheco; Enrique Perez-Cardenas; Lucia Taja-Chayeb; Lucely Cetina; Myrna Candelaria; David Cantu; Aurora Gonzalez-Fierro; Patricia Garcia-Lopez; Pilar Zambrano; Carlos Perez-Plasencia; Gustavo Cabrera; Catalina Trejo-Becerril; Enrique Angeles; Alfonso Duenas-Gonzalez

2005-01-01

112

Loss of Deacetylation Activity of Hdac6 Affects Emotional Behavior in Mice  

Microsoft Academic Search

Acetylation is mediated by acetyltransferases and deacetylases, and occurs not only on histones but also on diverse proteins. Although histone acetylation in chromatin structure and transcription has been well studied, the biological roles of non-histone acetylation remain elusive. Histone deacetylase 6 (Hdac6), a member of the histone deacetylase (HDAC) family, is a unique deacetylase that localizes to cytoplasm and functions

Masahide Fukada; Atsuko Hanai; Atsuo Nakayama; Takayoshi Suzuki; Naoki Miyata; Ramona M. Rodriguiz; William C. Wetsel; Tso-Pang Yao; Yoshiharu Kawaguchi

2012-01-01

113

Histone Deacetylase Inhibitors: Inducers of Differentiation or Apoptosis of Transformed Cells  

Microsoft Academic Search

Histone deacetylase (HDAC) inhibitors have been shown to be potent inducers of growth arrest, differentiation, and\\/or apoptotic cell death of transformed cells in vitro and in vivo. One class of HDAC inhibitors, hydroxamic acid-based hy- brid polar compounds (HPCs), induce differentiation at mi- cromolar or lower concentrations. Studies (x-ray crystallo- graphic) showed that the catalytic site of HDAC has a

Paul A. Marks; Victoria M. Richon; Richard A. Rifkind

114

The Therapeutic Potential of Class I Selective Histone Deacetylase Inhibitors in Ovarian Cancer  

PubMed Central

Epithelial ovarian cancer remains the deadliest gynecologic malignancy. Despite advances in treatment, new approaches are needed. Histone deacetylases (HDACs) are a family of enzymes that regulate gene expression by removing acetyl groups from lysine residues on histones and non-histone proteins. Inhibition of HDACs with small molecules has led to the development of histone deacetylase inhibitors (HDACi) that are in clinical use, primarily for hematologic malignancies. Although clinical trials with HDACi as single agents in solid tumors have been disappointing, data from independent labs and recent work by our group show that class I selective HDACi have potent anti-tumor effects in pre-clinical models of ovarian cancer. This review summarizes the role of HDACs in ovarian cancer and the potential niche for selective class I HDACi, particularly HDAC3 in ovarian cancer therapy. PMID:24904826

Khabele, Dineo

2014-01-01

115

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

116

Endogenous Inhibition of Histone Deacetylase 1 by Tumor-Suppressive Maspin  

Microsoft Academic Search

Maspin, a noninhibitory serine protease inhibitor, exerts multifaceted tumor-suppressive effects. Maspin expression is associated with better differentiated phenotypes, better cancer prognosis, and better drug sensitivity. Consistently, maspin also correlates with increased expression of Bax and p21WAF1\\/CIP1. Interestingly, histone deacetylase 1 (HDAC1), a major HDAC responsible for histone deacetylation, was shown to interact with maspin in a yeast two-hybrid screening. In

Xiaohua Li; Yonghong Meng; Wael Sakr; Shijie Sheng

117

Histone deacetylases—an important class of cellular regulators with a variety of functions  

Microsoft Academic Search

The elucidation of mechanisms of chromatin remodeling, particular transcriptional activation, and repression by histone acetylation\\u000a and deacetylation has shed light on the role of histone deacetylases (HDAC) as a new kind of therapeutic target for human\\u000a cancer treatment. HDACs, in general, act as components of large corepressor complexes that prevent the transcription of several\\u000a tumor suppression genes. In addition, they

Christian Hildmann; Daniel Riester; Andreas Schwienhorst

2007-01-01

118

Role of histone acetyltransferases and histone deacetylases in adipocyte differentiation and adipogenesis.  

PubMed

Adipogenesis is a complex process strictly regulated by a well-established cascade that has been thoroughly studied in the last two decades. This process is governed by complex regulatory networks that involve the activation/inhibition of multiple functional genes, and is controlled by histone-modifying enzymes. Among such modification enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs) play important roles in the transcriptional regulation and post-translational modification of protein acetylation. HATs and HDACs have been shown to respond to signals that regulate cell differentiation, participate in the regulation of protein acetylation, mediate transcription and post-translation modifications, and directly acetylate/deacetylate various transcription factors and regulatory proteins. In this paper, we review the role of HATs and HDACs in white and brown adipocyte differentiation and adipogenesis, to expand our knowledge on fat formation and adipose tissue biology. PMID:24810880

Zhou, Yuanfei; Peng, Jian; Jiang, Siwen

2014-04-01

119

A Role for Histone Deacetylases in the Cellular and Behavioral Mechanisms Underlying Learning and Memory  

ERIC Educational Resources Information Center

Histone deacetylases (HDACs) are a family of chromatin remodeling enzymes that restrict access of transcription factors to the DNA, thereby repressing gene expression. In contrast, histone acetyltransferases (HATs) relax the chromatin structure allowing for an active chromatin state and promoting gene transcription. Accumulating data have…

Mahgoub, Melissa; Monteggia, Lisa M.

2014-01-01

120

Aurora B-dependent Regulation of Class IIa Histone Deacetylases by Mitotic Nuclear Localization Signal Phosphorylation*  

PubMed Central

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.

2012-01-01

121

Selectively Targeting Prostate Cancer with Antiandrogen Equipped Histone Deacetylase Inhibitors  

PubMed Central

Diverse cellular processes relevant to cancer progression are regulated by the acetylation status of proteins. Among such processes is chromatin remodeling via histone proteins, controlled by opposing histone deacetylase (HDAC) and histone acetyltransferase (HAT) enzymes. Histone deacetylase inhibitors (HDACi) show great promise in preclinical cancer models, but clinical trials treating solid tumors have failed to improve patient survival. This is due in part to an inability of HDACi to effectively accumulate in cancerous cells. To address this problem we designed HDACi with secondary pharmacophores to facilitate selective accumulation in malignant cells. We present the first example of HDACi compounds targeted to prostate tumors by equipping them with the additional ability to bind the androgen receptor (AR) with non-steroidal antiandrogen moieties. Leads among these new dual-acting molecules bind to the AR and halt AR transcriptional activity at lower concentrations than clinical antiandrogens. They inhibit key isoforms of HDAC with low nanomolar potency. Fluorescent microscopy reveals varying degrees of AR nuclear localization in response to these compounds that correlates with their HDAC activity. These biological properties translate into potent anticancer activity against hormone dependent (AR+) LNCaP and to a lesser extent against hormone independent (AR?) DU145 prostate cancer, while having greatly reduced toxicity in non-cancerous cells. This illustrates that engaging multiple biological targets with a single chemical probe can achieve both potent and cell-type selective responses. PMID:24004176

Gryder, Berkley E.; Akbashev, Michelle J.; Rood, Michael K.; Raftery, Eric D.; Meyers, Warren M.; Dillard, Paulette; Khan, Shafiq; Oyelere, Adegboyega K.

2013-01-01

122

Mice lacking histone deacetylase 6 have hyperacetylated tubulin but are viable and develop normally.  

PubMed

Posttranslational modifications play important roles in regulating protein structure and function. Histone deacetylase 6 (HDAC6) is a mostly cytoplasmic class II HDAC, which has a unique structure with two catalytic domains and a domain binding ubiquitin with high affinity. This enzyme was recently identified as a multisubstrate protein deacetylase that can act on acetylated histone tails, alpha-tubulin and Hsp90. To investigate the in vivo functions of HDAC6 and the relevance of tubulin acetylation/deacetylation, we targeted the HDAC6 gene by homologous recombination in embryonic stem cells and generated knockout mice. HDAC6-deficient mice are viable and fertile and show hyperacetylated tubulin in most tissues. The highest level of expression of HDAC6 is seen in the testis, yet development and function of this organ are normal in the absence of HDAC6. Likewise, lymphoid development is normal, but the immune response is moderately affected. Furthermore, the lack of HDAC6 results in a small increase in cancellous bone mineral density, indicating that this deacetylase plays a minor role in bone biology. HDAC6-deficient mouse embryonic fibroblasts show apparently normal microtubule organization and stability and also show increased Hsp90 acetylation correlating with impaired Hsp90 function. Collectively, these data demonstrate that mice survive well without HDAC6 and that tubulin hyperacetylation is not detrimental to normal mammalian development. PMID:18180281

Zhang, Yu; Kwon, Sohee; Yamaguchi, Teppei; Cubizolles, Fabien; Rousseaux, Sophie; Kneissel, Michaela; Cao, Chun; Li, Na; Cheng, Hwei-Ling; Chua, Katrin; Lombard, David; Mizeracki, Adam; Matthias, Gabriele; Alt, Frederick W; Khochbin, Saadi; Matthias, Patrick

2008-03-01

123

Immunomodulatory effects of histone deacetylase inhibitors.  

PubMed

Histone deacetylase inhibitors (HDACi) have emerged as a new generation of anticancer therapeutics. The classical broad-spectrum HDACi typically alter the cell cycle distribution and induce cell death, apoptosis and differentiation in malignant and transformed cells. This provides the basis for the clinical potential of HDACi in cancer therapy. Currently two compounds, suberoylanilide hydroxamic acid (SAHA, Vorinostat, Zolinza™) and depsipeptide (Romidepsin, Istodax™) have been approved for by the US Food and Drug Administration for the treatment of refractory cutaneous T-cell lymphoma. Apart from clinical application in oncology, HDACi have also been investigated as potential therapeutics for various pathologies including those of the central nervous system (such as Huntington's disease and multiple sclerosis), cardiac conditions (particularly hypertrophy), arthritis and malaria. Further, evidence is accumulating for potent immunomodulatory effects of classical HDACi which is the focus of this review. We review the antiinflammatory effects of HDACi and in particular findings implicating regulation of the innate and adaptive immune systems by HDAC enzymes. The recent findings highlighting the immunomodulatory function of HDAC11 which relates to balancing immune activation versus tolerance are also discussed. PMID:23061676

Licciardi, P V; Ververis, K; Tang, M L; El-Osta, A; Karagiannis, T C

2013-05-01

124

Chromosomal organization and localization of the novel class IV human histone deacetylase 11 gene.  

PubMed

Histone deacetylases (HDACs) play a central role in the modification of chromatin structure and thus in the regulation of transcription and cellular differentiation. Based on structural and functional similarities, mammalian histone deacetylases may be grouped into four categories: class I HDACs, which are homologs of the yeast histone deacetylase RPD3; class II HDACs, which share a significant degree of homology with the yeast histone deacetylase HDA1; class III HDACs, which are closely related to the yeast SIR2 protein; and the most recently described class IV of HDACs, which comprises HDAC11-related enzymes. We have isolated and characterized the human HDAC11 genomic sequence, which spans a region of 24,074 bp and has a single genomic locus. Determination of the exon-intron splice junctions established that HDAC11 is encoded by 9 exons ranging in size from 43 bp (exon 4) to 867 bp (exon 9). Characterization of the 5' flanking genomic region, which precedes the HDAC11 open reading frame, revealed a TATA and CCAAT box-less promoter that contains a 1-kb CpG island. The 1,733-bp human HDAC11 mRNA encodes a 347 aa protein with a predictive molecular weight of 39.1 kDa and an isoelectric point of 6.88. Fluorescence in situ hybridization analysis localized the human HDAC11 gene to chromosome 3p25, a region characterized by frequent gains and losses of chromosomal material in a number of various types of cancer. PMID:16142391

Voelter-Mahlknecht, Susanne; Ho, Anthony D; Mahlknecht, Ulrich

2005-10-01

125

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

126

Epigenetics in anoxia tolerance: a role for histone deacetylases.  

PubMed

The importance of epigenetics has been established in many key biological processes but the relevance of this regulatory mechanism to animal survival of low oxygen conditions has never been examined. To establish whether epigenetic mechanisms could be involved in natural anoxia tolerance, we have examined the anoxia-responsive expression of the transcriptional silencers, histone deacetylases (HDACs), in tissues of a unique model for anoxia tolerance, the freshwater turtle Trachemys scripta elegans. Transcript and protein levels of all five HDACs rose by 1.3-4.6 and 1.7-3.5-fold, respectively, in skeletal muscle in response to 20 h of anoxia exposure. In addition, HDAC activity in the muscle increased by 1.5-fold in response to 20 h of anoxia and levels of acetylated histone H3 (Lys 9 or Lys 23) decreased to 40-60% of control values. The liver displayed a milder response with HDAC1, -4, and -5 protein levels increasing by 1.6-2.1-fold after 5 h anoxia exposure; acetylated histone H3 levels also decreased to 50-75% of control values. Only HDAC5 responded to anoxia exposure in the heart; Hdac5 transcript levels increased 2.1-2.3-fold and HDAC5 protein rose by 3.3-fold. Overall, our results show a tissue-specific pattern of HDAC upregulation in response to anoxia exposure in T.s. elegans, suggesting that these enzymes play a key role in anoxia tolerance, probably by contributing to the transcriptional silencing necessary in this hypometabolic state. PMID:20437082

Krivoruchko, Anastasia; Storey, Kenneth B

2010-09-01

127

Histone Acetylation and CREB Binding Protein Are Required for Neuronal Resistance against Ischemic Injury  

E-print Network

Epigenetic transcriptional regulation by histone acetylation depends on the balance between histone acetyltransferase (HAT) and deacetylase activities (HDAC). Inhibition of HDAC activity provides neuroprotection, indicating ...

Yildirim, Ferah

128

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

129

Non-Peptide Macrocyclic Histone Deacetylase Inhibitors Derived from Tricyclic Ketolide Skeleton  

PubMed Central

Inhibition of histone deacetylase (HDAC) function is a validated therapeutic strategy for cancer treatment. Of the several structurally distinct small molecule histone deacetylase inhibitors (HDACi) reported, macrocyclic depsipeptides possess the most complex cap-groups and have demonstrated excellent HDAC inhibition potency and isoform selectivity. Unfortunately, the development of macrocyclic depsipeptides has been hampered in part due to development problems characteristic of large peptides and the complex reaction schemes required for their synthesis. Herein we report that tricyclic ketolide TE-802 is an excellent mimetic for the peptide backbone of macrocyclic HDACi. Compounds derived from this template are particularly selective against HDAC 1 and 2 with nanomolar inhibitory activity. Interrogation of the association between a subset of these compounds and key HDAC isoforms, using AutoDock, enables a molecular description of the interaction between the HDAC enzyme's outer rim and the inhibitors’ macrocyclic cap group that are responsible for compound affinity and presumably isoform selectivity. PMID:20669972

Mwakwari, Sandra C.; Guerrant, William; Patil, Vishal; Khan, Shabana I.; Tekwani, Babu L.; Gurard-Levin, Zachary A.; Mrksich, Milan; Oyelere, Adegboyega K.

2010-01-01

130

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

131

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

132

Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis.  

PubMed

The development and severity of inflammatory bowel diseases and other chronic inflammatory conditions can be influenced by host genetic and environmental factors, including signals derived from commensal bacteria. However, the mechanisms that integrate these diverse cues remain undefined. Here we demonstrate that mice with an intestinal epithelial cell (IEC)-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 defence. 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 showed significantly increased susceptibility to intestinal damage and inflammation, indicating that epithelial expression of HDAC3 has a central role in maintaining intestinal homeostasis. Re-derivation 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. Although the specific mechanisms through which IEC-intrinsic HDAC3 expression regulates these complex phenotypes remain to be determined, 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

2013-12-01

133

Ex Vivo Response to Histone Deacetylase (HDAC) Inhibitors of the HIV Long Terminal Repeat (LTR) Derived from HIV-Infected Patients on Antiretroviral Therapy  

PubMed Central

Histone deacetylase inhibitors (HDACi) can induce human immunodeficiency virus (HIV) transcription from the HIV long terminal repeat (LTR). However, ex vivo and in vivo responses to HDACi are variable and the activity of HDACi in cells other than T-cells have not been well characterised. Here, we developed a novel assay to determine the activity of HDACi on patient-derived HIV LTRs in different cell types. HIV LTRs from integrated virus were amplified using triple-nested Alu-PCR from total memory CD4+ T-cells (CD45RO+) isolated from HIV-infected patients prior to and following suppressive antiretroviral therapy. NL4-3 or patient-derived HIV LTRs were cloned into the chromatin forming episomal vector pCEP4, and the effect of HDACi investigated in the astrocyte and epithelial cell lines SVG and HeLa, respectively. There were no significant differences in the sequence of the HIV LTRs isolated from CD4+ T-cells prior to and after 18 months of combination antiretroviral therapy (cART). We found that in both cell lines, the HDACi panobinostat, trichostatin A, vorinostat and entinostat activated patient-derived HIV LTRs to similar levels seen with NL4-3 and all patient derived isolates had similar sensitivity to maximum HDACi stimulation. We observed a marked difference in the maximum fold induction of luciferase by HDACi in HeLa and SVG, suggesting that the effect of HDACi may be influenced by the cellular environment. Finally, we observed significant synergy in activation of the LTR with vorinostat and the viral protein Tat. Together, our results suggest that the LTR sequence of integrated virus is not a major determinant of a functional response to an HDACi. PMID:25409334

Lu, Hao K.; Gray, Lachlan R.; Wightman, Fiona; Ellenberg, Paula; Khoury, Gabriela; Cheng, Wan-Jung; Mota, Talia M.; Wesselingh, Steve; Gorry, Paul R.; Cameron, Paul U.

2014-01-01

134

Computational design of a time-dependent histone deacetylase 2 selective inhibitor.  

PubMed

Development of isoform-selective histone deacetylase (HDAC) inhibitors is of great biological and medical interest. Among 11 zinc-dependent HDAC isoforms, it is particularly challenging to achieve isoform inhibition selectivity between HDAC1 and HDAC2 due to their very high structural similarities. In this work, by developing and applying a novel de novo reaction-mechanism-based inhibitor design strategy to exploit the reactivity difference, we have discovered the first HDAC2-selective inhibitor, ?-hydroxymethyl chalcone. Our bioassay experiments show that this new compound has a unique time-dependent selective inhibition on HDAC2, leading to about 20-fold isoform-selectivity against HDAC1. Furthermore, our ab initio QM/MM molecular dynamics simulations, a state-of-the-art approach to study reactions in biological systems, have elucidated how the ?-hydroxymethyl chalcone can achieve the distinct time-dependent inhibition toward HDAC2. PMID:25546141

Zhou, Jingwei; Li, Min; Chen, Nanhao; Wang, Shenglong; Luo, Hai-Bin; Zhang, Yingkai; Wu, Ruibo

2015-03-20

135

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

136

Histone deacetylase inhibitors as novel anticancer therapeutics  

PubMed Central

Histone deacetylase inhibitors represent a promising new class of compounds for the treatment of cancer. Inhibitors of this kind currently under clinical evaluation mainly target the classical (Rpd3/Hda1) family of histone deacetylases. Of particular note, the U.S. Food and Drug Administration recently approved the first histone deacetylase inhibitor (Zolinza: Merck and Co., Whitehouse Station, NJ, U.S.A.) for the treatment of cutaneous T-cell lymphoma. Dozens of such inhibitors are now in phase ii–iii clinical trials, sometimes in combination with other chemotherapy drugs, for diverse cancer types, including both hematologic and solid tumours. In this mini-review, we provide an overview of the histone deacetylase superfamily, highlight the positive results of deacetylase inhibitors in cancer clinical trials, and comment on the prospects for the next generation of such inhibitors. PMID:19008999

Walkinshaw, D.R.; Yang, X.J.

2008-01-01

137

Loss of histone deacetylase 2 improves working memory and accelerates extinction learning  

PubMed Central

Histone acetylation and deacetylation can be dynamically regulated in response to environmental stimuli and play important roles in learning and memory. Pharmacological inhibition of histone deacetylases (HDACs) improves performance in learning tasks, however these classical agents are ‘pan-HDAC’ inhibitors and their use makes it difficult to determine the roles of specific HDACs in cognitive function. We took a genetic approach using mice lacking the class I HDACs, HDAC1 or HDAC2, in postmitotic forebrain neurons to investigate the specificity or functional redundancy of these HDACs in learning and synaptic plasticity. We show that selective knockout of HDAC2 led to a robust acceleration of the extinction rate of conditioned fear responses and a conditioned taste aversion as well as enhanced performance in an attentional set-shifting task. HDAC2 knockout had no impact on episodic memory or motor learning suggesting that the effects are task-dependent, with the predominant impact of HDAC2 inhibition being an enhancement in an animal’s ability to rapidly adapt its behavioral strategy as a result of changes in associative contingencies. Our results demonstrate that the loss of HDAC2 improves associative learning, with no effect in non-associative learning tasks, suggesting a specific role for HDAC2 in particular types of learning. HDAC2 may be an intriguing target for cognitive and psychiatric disorders that are characterized by an inability to inhibit behavioral responsiveness to maladaptive or no longer relevant associations. PMID:23575838

Morris, Michael J.; Mahgoub, Melissa; Na, Elisa S.; Pranav, Heena; Monteggia, Lisa. M.

2013-01-01

138

HdaA, a Major Class 2 Histone Deacetylase of Aspergillus nidulans, Affects Growth under Conditions of Oxidative Stress  

Microsoft Academic Search

Histone deacetylases (HDACs) catalyze the removal of acetyl groups from the -amino group of distinct lysine residues in the amino-terminal tail of core histones. Since the acetylation status of core histones plays a crucial role in fundamental processes in eukaryotic organisms, such as replication and regulation of transcription, recent research has focused on the enzymes responsible for the acetylation\\/deacetylation of

Martin Tribus; Johannes Galehr; Patrick Trojer; Gerald Brosch; Peter Loidl; Florentine Marx; Hubertus Haas; Stefan Graessle

2005-01-01

139

Remodeling Chromatin and Stress Resistance in the Central Nervous System: Histone Deacetylase Inhibitors as Novel and Broadly Effective Neuroprotective Agents  

Microsoft Academic Search

Acetylation and deacetylation of histone protein plays a critical role in regulating gene expression in a host of biological processes including cellular proliferation, development, and differentiation. Accordingly, aberrant acetylation and deacetylation resulting from the misregulation of histone acetyltransferases (HATs) and\\/or histone deacetylases (HDACs) has been linked to clinical disorders such as Rubinstein-Taybi syndrome, fragile X syndrome, leukemia, and various cancers.

Brett Langley; JoAnn M. Gensert; M. Flint Beal; Rajiv R. Ratan

2005-01-01

140

Dysregulation of Histone Acetyltransferases and Deacetylases in Cardiovascular Diseases  

PubMed Central

Cardiovascular disease (CVD) remains a leading cause of mortality worldwide despite advances in its prevention and management. A comprehensive understanding of factors which contribute to CVD is required in order to develop more effective treatment options. Dysregulation of epigenetic posttranscriptional modifications of histones in chromatin is thought to be associated with the pathology of many disease models, including CVD. Histone acetyltransferases (HATs) and deacetylases (HDACs) are regulators of histone lysine acetylation. Recent studies have implicated a fundamental role of reversible protein acetylation in the regulation of CVDs such as hypertension, pulmonary hypertension, diabetic cardiomyopathy, coronary artery disease, arrhythmia, and heart failure. This reversible acetylation is governed by enzymes that HATs add or HDACs remove acetyl groups respectively. New evidence has revealed that histone acetylation regulators blunt cardiovascular and related disease states in certain cellular processes including myocyte hypertrophy, apoptosis, fibrosis, oxidative stress, and inflammation. The accumulating evidence of the detrimental role of histone acetylation in cardiac disease combined with the cardioprotective role of histone acetylation regulators suggests that the use of histone acetylation regulators may serve as a novel approach to treating the millions of patients afflicted by cardiac diseases worldwide. PMID:24693336

Wang, Yonggang; Miao, Xiao; Liu, Yucheng; Li, Fengsheng; Liu, Quan; Sun, Jian; Cai, Lu

2014-01-01

141

Histone Deacetylase Inhibitors Enhance Memory and Synaptic Plasticity via CREB: CBP-Dependent Transcriptional Activation  

PubMed Central

Histone deacetylase (HDAC) inhibitors increase histone acetylation and enhance both memory and synaptic plasticity. The current model for the action of HDAC inhibitors assumes that they alter gene expression globally and thus affect memory processes in a nonspecific manner. Here, we show that the enhancement of hippocampus-dependent memory and hippocampal synaptic plasticity by HDAC inhibitors is mediated by the transcription factor cAMP response element-binding protein (CREB) and the recruitment of the transcriptional coactivator and histone acetyltransferase CREB-binding protein (CBP) via the CREB-binding domain of CBP. Furthermore, we show that the HDAC inhibitor trichostatin A does not globally alter gene expression but instead increases the expression of specific genes during memory consolidation. Our results suggest that HDAC inhibitors enhance memory processes by the activation of key genes regulated by the CREB:CBP transcriptional complex. PMID:17553985

Vecsey, Christopher G.; Hawk, Joshua D.; Lattal, K. Matthew; Stein, Joel M.; Fabian, Sara A.; Attner, Michelle A.; Cabrera, Sara M.; McDonough, Conor B.; Brindle, Paul K.; Abel, Ted; Wood, Marcelo A.

2010-01-01

142

Vascular histone deacetylation by pharmacological HDAC inhibition  

PubMed Central

HDAC inhibitors can regulate gene expression by post-translational modification of histone as well as nonhistone proteins. Often studied at single loci, increased histone acetylation is the paradigmatic mechanism of action. However, little is known of the extent of genome-wide changes in cells stimulated by the hydroxamic acids, TSA and SAHA. In this article, we map vascular chromatin modifications including histone H3 acetylation of lysine 9 and 14 (H3K9/14ac) using chromatin immunoprecipitation (ChIP) coupled with massive parallel sequencing (ChIP-seq). Since acetylation-mediated gene expression is often associated with modification of other lysine residues, we also examined H3K4me3 and H3K9me3 as well as changes in CpG methylation (CpG-seq). RNA sequencing indicates the differential expression of ?30% of genes, with almost equal numbers being up- and down-regulated. We observed broad deacetylation and gene expression changes conferred by TSA and SAHA mediated by the loss of EP300/CREBBP binding at multiple gene promoters. This study provides an important framework for HDAC inhibitor function in vascular biology and a comprehensive description of genome-wide deacetylation by pharmacological HDAC inhibition. PMID:24732587

Rafehi, Haloom; Balcerczyk, Aneta; Lunke, Sebastian; Kaspi, Antony; Ziemann, Mark; KN, Harikrishnan; Okabe, Jun; Khurana, Ishant; Ooi, Jenny; Khan, Abdul Waheed; Chang, Lisa; Haviv, Izhak; Keating, Samuel T.; Karagiannis, Tom C.

2014-01-01

143

Vascular histone deacetylation by pharmacological HDAC inhibition.  

PubMed

HDAC inhibitors can regulate gene expression by post-translational modification of histone as well as nonhistone proteins. Often studied at single loci, increased histone acetylation is the paradigmatic mechanism of action. However, little is known of the extent of genome-wide changes in cells stimulated by the hydroxamic acids, TSA and SAHA. In this article, we map vascular chromatin modifications including histone H3 acetylation of lysine 9 and 14 (H3K9/14ac) using chromatin immunoprecipitation (ChIP) coupled with massive parallel sequencing (ChIP-seq). Since acetylation-mediated gene expression is often associated with modification of other lysine residues, we also examined H3K4me3 and H3K9me3 as well as changes in CpG methylation (CpG-seq). RNA sequencing indicates the differential expression of ?30% of genes, with almost equal numbers being up- and down-regulated. We observed broad deacetylation and gene expression changes conferred by TSA and SAHA mediated by the loss of EP300/CREBBP binding at multiple gene promoters. This study provides an important framework for HDAC inhibitor function in vascular biology and a comprehensive description of genome-wide deacetylation by pharmacological HDAC inhibition. PMID:24732587

Rafehi, Haloom; Balcerczyk, Aneta; Lunke, Sebastian; Kaspi, Antony; Ziemann, Mark; Kn, Harikrishnan; Okabe, Jun; Khurana, Ishant; Ooi, Jenny; Khan, Abdul Waheed; Du, Xiao-Jun; Chang, Lisa; Haviv, Izhak; Keating, Samuel T; Karagiannis, Tom C; El-Osta, Assam

2014-08-01

144

Cell Growth Inhibition and Gene Expression Induced by the Histone Deacetylase Inhibitor, Trichostatin A, on Human Hepatoma Cells  

Microsoft Academic Search

Objective: Histone deacetylase (HDAC) inhibitors have been reported to induce cell growth arrest, apoptosis and differentiation in tumor cells. The effect of the HDAC inhibitor, trichostatin A (TSA), on hepatoma cells, however, has not been well studied. In this study, we examined cell viability and gene expression profile in hepatoma cell lines treated with TSA. Methods: To study cell growth

Tetsuhiro Chiba; Osamu Yokosuka; Kenichi Fukai; Hiroshige Kojima; Motohisa Tada; Makoto Arai; Fumio Imazeki; Hiromitsu Saisho

2004-01-01

145

Histone deacetylases as therapeutic targets--from cancer to cardiac disease.  

PubMed

Heart failure is a major public health problem in western society. Recently, agents that inhibit histone deacetylase (HDAC) enzymes were developed and approved by the FDA as anticancer agents. This breakthrough has provided the motivation to develop more potent and more selective HDAC inhibitors and to target other pathologic conditions with these drugs. Here we review experimental evidence showing that these drugs may be beneficial in preventing cardiac hypertrophy and heart failure. Several lines of evidence show that inhibitors of Class I HDACs can blunt cardiac hypertrophy and preserve cardiac function in several small animal models. In contrast, Class IIa HDACs appear to be suppressors of hypertrophy, though experimental data with small molecule blockers of this class is largely lacking. The effects of HDAC inhibition in cardiac diseases, the cell population in the heart that is targeted by HDAC blockers, as well as the relative roles of specific HDACs are still under intense investigation. PMID:25444758

Abend, Alon; Kehat, Izhak

2015-03-01

146

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

147

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

148

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

149

Inhibitors of histone deacetylases enhance neurotoxicity of DNA damage.  

PubMed

The nonselective inhibitors of class I/II histone deacetylases (HDACs) including trichostatin A and the clinically used suberoylanilide hydroxamic acid (SAHA, vorinostat) are neuroprotective in several models of neuronal injury. Here, we report that in cultured cortical neurons from newborn rats and in the cerebral cortex of whole neonate rats, these HDAC inhibitors exacerbated cytotoxicity of the DNA double-strand break (DSB)-inducing anticancer drug etoposide by enhancing apoptosis. Similar neurotoxic interactions were also observed in neurons that were treated with other DNA damaging drugs including cisplatin and camptothecin. In addition, in rat neonates, SAHA increased cortical neuron apoptosis that was induced by a single injection of the NMDA receptor antagonist dizocilpine (MK801). In etoposide-treated neurons, the nonselective HDAC inhibition resulted in more DSBs. It also potentiated etoposide-induced accumulation and phosphorylation of the pro-apoptotic transcription factor p53. Moreover, nonselective HDAC inhibition exacerbated neuronal apoptosis that was induced by the overexpressed p53. Importantly, such effects cannot be fully explained by inhibition of HDAC1, which is known to play a role in DSB repair and regulation of p53. The specific HDAC1 inhibitor MS275 only moderately enhanced etoposide-induced neuronal death. Although in etoposide-treated neurons MS275 increased DSBs, it did not affect activation of p53. Our findings suggest that besides HDAC1, there are other class I/II HDACs that participate in neuronal DNA damage response attenuating neurotoxic consequences of genotoxic insults to the developing brain. PMID:25063076

Vashishta, A; Hetman, M

2014-12-01

150

Histone deacetylase 4 selectively contributes to podocyte injury in diabetic nephropathy.  

PubMed

Studies have highlighted the importance of histone deacetylase (HDAC)-mediated epigenetic processes in the development of diabetic complications. Inhibitors of HDAC are a novel class of therapeutic agents in diabetic nephropathy, but currently available inhibitors are mostly nonselective inhibit multiple HDACs, and different HDACs serve very distinct functions. Therefore, it is essential to determine the role of individual HDACs in diabetic nephropathy and develop HDAC inhibitors with improved specificity. First, we identified the expression patterns of HDACs and found that, among zinc-dependent HDACs, HDAC2/4/5 were upregulated in the kidney from streptozotocin-induced diabetic rats, diabetic db/db mice, and in kidney biopsies from diabetic patients. Podocytes treated with high glucose, advanced glycation end products, or transforming growth factor-? (common detrimental factors in diabetic nephropathy) selectively increased HDAC4 expression. The role of HDAC4 was evaluated by in vivo gene silencing by intrarenal lentiviral gene delivery and found to reduce renal injury in diabetic rats. Podocyte injury was associated with suppressing autophagy and exacerbating inflammation by HDAC4-STAT1 signaling in vitro. Thus, HDAC4 contributes to podocyte injury and is one of critical components of a signal transduction pathway that links renal injury to autophagy in diabetic nephropathy. PMID:24717296

Wang, Xiaojie; Liu, Jiang; Zhen, Junhui; Zhang, Chun; Wan, Qiang; Liu, Guangyi; Wei, Xinbing; Zhang, Yan; Wang, Ziying; Han, Huirong; Xu, Huiyan; Bao, Chanchan; Song, Zhenyu; Zhang, Xiumei; Li, Ningjun; Yi, Fan

2014-10-01

151

Histone Deacetylase 3 Promotes RCAN1 Stability and Nuclear Translocation  

PubMed Central

Regulator of calcineurin 1 (RCAN1; also referred as DSCR1 or MCIP1) is located in close proximity to a Down syndrome critical region of human chromosome 21. Although RCAN1 is an endogenous inhibitor of calcineurin signaling that controls lymphocyte activation, apoptosis, heart development, skeletal muscle differentiation, and cardiac function, it is not yet clear whether RCAN1 might be involved in other cellular activities. In this study, we explored the extra-functional roles of RCAN1 by searching for novel RCAN1-binding partners. Using a yeast two-hybrid assay, we found that RCAN1 (RCAN1-1S) interacts with histone deacetylase 3 (HDAC3) in mammalian cells. We also demonstrate that HDAC3 deacetylates RCAN1. In addition, HDAC3 increases RCAN1 protein stability by inhibiting its poly-ubiquitination. Furthermore, HDAC3 promotes RCAN1 nuclear translocation. These data suggest that HDAC3, a new binding regulator of RCAN1, affects the protein stability and intracellular localization of RCAN1. PMID:25144594

Han, Kyung Ah; Kang, Hye Seon; Lee, Jee Won; Yoo, Lang; Im, Eunju; Hong, Ahyoung; Lee, Yun Ju; Shin, Woo Hyun; Chung, Kwang Chul

2014-01-01

152

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

2015-03-01

153

Systemic or Intrahippocampal Delivery of Histone Deacetylase Inhibitors Facilitates Fear Extinction  

E-print Network

Systemic or Intrahippocampal Delivery of Histone Deacetylase Inhibitors Facilitates Fear Extinction and hippocampus-dependent memory. Little is known about the effects of HDAC inhibitors on extinction, a learning-min) contextual extinction session causes context-evoked fear to decrease to levels observed

Wood, Marcelo A.

154

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

155

Histone deacetylase 6 regulates growth factor-induced actin remodeling and endocytosis.  

PubMed

Histone deacetylase 6 (HDAC6) is a cytoplasmic deacetylase that uniquely catalyzes alpha-tubulin deacetylation and promotes cell motility. However, the mechanism underlying HDAC6-dependent cell migration and the role for microtubule acetylation in motility are not known. Here we show that HDAC6-induced global microtubule deacetylation was not sufficient to stimulate cell migration. Unexpectedly, in response to growth factor stimulation, HDAC6 underwent rapid translocation to actin-enriched membrane ruffles and subsequently became associated with macropinosomes, the vesicles for fluid-phase endocytosis. Supporting the importance of these associations, membrane ruffle formation, macropinocytosis, and cell migration were all impaired in HDAC6-deficient cells. Conversely, elevated HDAC6 levels promoted membrane ruffle formation with a concomitant increase in macropinocytosis and motility. In search for an HDAC6 target, we found that heat shock protein 90 (Hsp90), another prominent substrate of HDAC6, was also recruited to membrane ruffles and macropinosomes. Significantly, inhibition of Hsp90 activity suppressed membrane ruffling and cell migration, while expression of an acetylation-resistant Hsp90 mutant promoted ruffle formation. Our results uncover a surprising role for HDAC6 in actin remodeling-dependent processes and identify the actin cytoskeleton as an important target of HDAC6-regulated protein deacetylation. PMID:17938201

Gao, Ya-sheng; Hubbert, Charlotte C; Lu, Jianrong; Lee, Yi-Shan; Lee, Joo-Yong; Yao, Tso-Pang

2007-12-01

156

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

157

Expression Levels of Histone Deacetylases Determine the Cell Fate of Hematopoietic Progenitors*  

PubMed Central

Histone deacetylases (HDACs) are globally implicated in the growth and differentiation of mammalian cells; however, relatively little is known about their specific roles in hematopoiesis. In this study, we investigated the expression of HDACs in human hematopoietic cells and their functions during hematopoiesis. The expression of HDACs was very low in hematopoietic progenitor cells, which was accompanied by histone hyperacetylation. HDACs were detectable in more differentiated progenitors and erythroid precursors but down-regulated in mature myeloid cells especially granulocytes. In contrast, acute myeloid leukemias showed HDAC overexpression and histone hypoacetylation. Transcription of the HDAC1 gene was repressed by CCAAT/enhancer binding proteins during myeloid differentiation, and activated by GATA-1 during erythro-megakaryocytic differentiation. Small interfering RNA-mediated knockdown of HDAC1 enhanced myeloid differentiation in immature hematopoietic cell lines and perturbed erythroid differentiation in progenitor cells. Myeloid but not erythro-megakaryocytic differentiation was blocked in mice transplanted with HDAC1-overexpressing hematopoietic progenitor cells. These findings suggest that HDAC is not merely an auxiliary factor of genetic elements but plays a direct role in the cell fate decision of hematopoietic progenitors. PMID:19736310

Wada, Taeko; Kikuchi, Jiro; Nishimura, Noriko; Shimizu, Rumi; Kitamura, Toshio; Furukawa, Yusuke

2009-01-01

158

Histone deacetylase inhibitors: design, structure-activity relationships and therapeutic implications for cancer.  

PubMed

Histone deacetylases (HDACs) remove acetyl groups from the tails of lysine residues of histone protein in nuclear chromatin and also from acetylated sites in non-histone proteins. HDACs and histone acetyltransferases (HATs) are major influences on the level of cellular protein acetylation, and an imbalance in acetylation levels, particularly under-acetylated (hypoacetylated) histone protein has been associated with precancerous or malignant states. Consequently, small molecule inhibitors of HDACs have been synthesised and some now form a newly emerging class of anti-cancer agents that can regulate transcription and inhibit proliferation of cancer cells by inducing cell cycle arrest, differentiation and/or apoptosis, among other major biological phenomena. The different mechanism(s) of action of HDAC inhibitors compared to conventional anti-neoplastic agents provides a possibility that HDAC inhibitors may be effective for refractory cancers. Accordingly, a number of programs for the development of HDAC inhibitors as anti-cancer drugs have been initiated. This review highlights recent developments in the design, synthesis and biological properties of HDAC inhibitors in the context of potential cancer therapy. PMID:19601748

Marson, Charles M

2009-07-01

159

Cigarette smoking reduces histone deacetylase 2 expression, enhances cytokine expression, and inhibits glucocorticoid actions in alveolar macrophages  

Microsoft Academic Search

Cigarette smoke is the major cause of chronic obstructive pulmonary disease (COPD), a chronic inflammatory disease of the airway. The increased expression of inflammatory proteins results from enhanced gene transcription, as these mediators are induced in a cell-specific manner. Changes in transcription depend on chromatin remodeling and the relative activities of histone acetyl-transferases (HATs) and histone deacetylases (HDACs). We have

K. Ito; S. Lim; G. Caramori; K. F. Chung; P. J. Barnes; I. M. Adcock

2001-01-01

160

Targeting histone deacetylases: perspectives for epigenetic-based therapy in cardio-cerebrovascular disease  

PubMed Central

Although the pathogenesis of cardio-cerebrovascular disease (CCVD) is multifactorial, an increasing number of experimental and clinical studies have highlighted the importance of histone deacetylase (HDAC)-mediated epigenetic processes in the development of cardio-cerebrovascular injury. HDACs are a family of enzymes to balance the acetylation activities of histone acetyltransferases on chromatin remodeling and play essential roles in regulating gene transcription. To date, 18 mammalian HDACs are identified and grouped into four classes based on similarity to yeast orthologs. The zinc-dependent HDAC family currently consists of 11 members divided into three classes (class I, II, and IV) on the basis of structure, sequence homology, and domain organization. In comparison, class III HDACs (also known as the sirtuins) are composed of a family of NAD+-dependent protein-modifying enzymes related to the Sir2 gene. HDAC inhibitors are a group of compounds that block HDAC activities typically by binding to the zinc-containing catalytic domain of HDACs and have displayed anti-inflammatory and antifibrotic effects in the cardio-cerebrovascular system. In this review, we summarize the current knowledge about classifications, functions of HDACs and their roles and regulatory mechanisms in the cardio-cerebrovascular system. Pharmacological targeting of HDAC-mediated epigenetic processes may open new therapeutic avenues for the treatment of CCVD. PMID:25870619

Wang, Zi-Ying; Qin, Wen; Yi, Fan

2015-01-01

161

Drosophila Histone Deacetylase-3 Controls Imaginal Disc Size through Suppression of Apoptosis  

PubMed Central

Histone deacetylases (HDACs) execute biological regulation through post-translational modification of chromatin and other cellular substrates. In humans, there are eleven HDACs, organized into three distinct subfamilies. This large number of HDACs raises questions about functional overlap and division of labor among paralogs. In vivo roles are simpler to address in Drosophila, where there are only five HDAC family members and only two are implicated in transcriptional control. Of these two, HDAC1 has been characterized genetically, but its most closely related paralog, HDAC3, has not. Here we describe the isolation and phenotypic characterization of hdac3 mutations. We find that both hdac3 and hdac1 mutations are dominant suppressors of position effect variegation, suggesting functional overlap in heterochromatin regulation. However, all five hdac3 loss-of-function alleles are recessive lethal during larval/pupal stages, indicating that HDAC3 is essential on its own for Drosophila development. The mutant larvae display small imaginal discs, which result from abnormally elevated levels of apoptosis. This cell death occurs as a cell-autonomous response to HDAC3 loss and is accompanied by increased expression of the pro-apoptotic gene, hid. In contrast, although HDAC1 mutants also display small imaginal discs, this appears to result from reduced proliferation rather than from elevated apoptosis. The connection between HDAC loss and apoptosis is important since HDAC inhibitors show anticancer activities in animal models through mechanisms involving apoptotic induction. However, the specific HDACs implicated in tumor cell killing have not been identified. Our results indicate that protein deacetylation by HDAC3 plays a key role in suppression of apoptosis in Drosophila imaginal tissue. PMID:18454196

Zhitomirsky, David; Miller, Ellen L.; O'Connor, Michael B.; Simon, Jeffrey A.

2008-01-01

162

Synergetic effects of DNA demethylation and histone deacetylase inhibition in primary rat hepatocytes  

Microsoft Academic Search

Summary  Both, DNA methylation and histone deacetylation play a crucial role in cancer development by silencing the expression of specific\\u000a tumour suppressor genes. Several studies describe the use of combinations of DNA methyltransferase inhibitors (DNMT-i) and\\u000a histone deacetylase inhibitors (HDAC-i) as an improved strategy to treat neoplasms. However, no information is available concerning\\u000a their biological impact on healthy, non-malignant cells, including

Joanna Edyta Fraczek; Mathieu Vinken; Dirk Tourwé; Tamara Vanhaecke; Vera Rogiers

163

Modulation of immune responses by histone deacetylase inhibitors.  

PubMed

Recent studies have demonstrated that histone deacetylase (HDAC) inhibitors (HDACi) have potential immunomodulatory activity since they affect the immune surveillance by regulating the production of cytokines, alter the activity and function of macrophages and dendritic cells (DC), regulate the transcription of a variety of immune-stimulating genes, and can modulate the activity of immune effector cells of both the innate and adaptive immune system. Besides their immunostimulatory activity, HDACi can induce growth arrest and cell death, and modulate a subset of cellular functions such as cell motility or differentiation. This makes HDACi interesting therapeutic candidates for the treatment of a variety of human diseases like cancer, autoimmune, and graft versus host diseases. Besides these, HDACs have been shown to be involved in virus replication and pathogenesis, and it was recently shown that HDACi provide therapeutic effects in the treatment of oncogenic virus infections and associated malignancies. This review will further give information about the different families of HDACs and their opponents, the histone acetylases (HATs), about the classes and function of specific HDACi, and their use in the treatment of human diseases. PMID:25746108

Schotterl, Sonja; Brennenstuhl, Heiko; Naumann, Ulrike

2015-01-01

164

Type-II histone deacetylases: elusive plant nuclear signal transducers.  

PubMed

Since the beginning of the 21st century, numerous studies have concluded that the plant cell nucleus is one of the cellular compartments that define the specificity of the cellular response to an external stimulus or to a specific developmental stage. To that purpose, the nucleus contains all the enzymatic machinery required to carry out a wide variety of nuclear protein post-translational modifications (PTMs), which play an important role in signal transduction pathways leading to the modulation of specific sets of genes. PTMs include protein (de)acetylation which is controlled by the antagonistic activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Regarding protein deacetylation, plants are of particular interest: in addition to the RPD3-HDA1 and Sir2 HDAC families that they share with other eukaryotic organisms, plants have developed a specific family called type-II HDACs (HD2s). Interestingly, these HD2s are well conserved in plants and control fundamental biological processes such as seed germination, flowering or the response to pathogens. The aim of this review was to summarize current knowledge regarding this fascinating, but still poorly understood nuclear protein family. PMID:24236403

Grandperret, Vincent; Nicolas-Francès, Valérie; Wendehenne, David; Bourque, Stéphane

2014-06-01

165

A steered molecular dynamics mediated hit discovery for histone deacetylases.  

PubMed

The inhibitors of class I histone deacetylases (HDACIs) have gained significant interest in cancer therapeutics. Virtual high throughput screening (vHTS) is one of the popular approaches used in the identification of novel scaffolds of HDACIs. However, an accurate description of ligand-protein flexibilities in the vHTS remains challenging. In this work, we implement an integrated approach, which combines the vHTS with the 'state-of-the-art' steered molecular dynamics (SMD). This approach serves as an efficient tool to identify potential hits and characterize their binding potencies against the class I HDACs in a flexible solvent environment. A hybrid pharmacophore-based and structure-based vHTS method identifies the hits with more favourable physico-chemical features against the class I HDACs. Our pharmacophore-based screening enhanced the quality of the vHTS outcomes. Further, the molecular interactions between the hits and the HDACs are investigated using the SMD-driven force profiles, which in turn resulted in filtering the hits with higher binding potencies against the HDACs. Our results, therefore, reveal that vHTS and SMD can be a complementary and effective analytical tool for accelerating the hit identification phase in structure-based drug design. PMID:24429775

Kalyaanamoorthy, Subha; Chen, Yi-Ping Phoebe

2014-02-28

166

Microarray deacetylation maps determine genome-wide functions for yeast histone deacetylases.  

PubMed

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 are used instead for gluconeogenesis, growth on carbon sources other than glucose, and adverse growth conditions. These domains have certain features of heterochromatin but are distinct from subtelomeric heterochromatin repressed by the deacetylase Sir2. Finally, Hos1/Hos3 and Hos2 preferentially affect ribosomal DNA and ribosomal protein genes, respectively. Thus, acetylation microarrays uncover the "division of labor" for yeast histone deacetylases. PMID:12086601

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

2002-05-17

167

A role for histone deacetylases in the cellular and behavioral mechanisms underlying learning and memory.  

PubMed

Histone deacetylases (HDACs) are a family of chromatin remodeling enzymes that restrict access of transcription factors to the DNA, thereby repressing gene expression. In contrast, histone acetyltransferases (HATs) relax the chromatin structure allowing for an active chromatin state and promoting gene transcription. Accumulating data have demonstrated a crucial function for histone acetylation and histone deacetylation in regulating the cellular and behavioral mechanisms underlying synaptic plasticity and learning and memory. In trying to delineate the roles of individual HDACs, genetic tools have been used to manipulate HDAC expression in rodents, uncovering distinct contributions of individual HDACs in regulating the processes of memory formation. Moreover, recent findings have suggested an important role for HDAC inhibitors in enhancing learning and memory processes as well as ameliorating symptoms related to neurodegenerative diseases. In this review, we focus on the role of HDACs in learning and memory, as well as significant data emerging from the field in support of HDAC inhibitors as potential therapeutic targets for the treatment of cognitive disorders. PMID:25227251

Mahgoub, Melissa; Monteggia, Lisa M

2014-10-01

168

Inhibition of histone deacetylase causes reduction of appressorium formation in the rice blast fungus Magnaporthe oryzae.  

PubMed

Post-translational modifications (PTMs) are important for cellular functions. The regulation of histone acetyltransferases (HATs) and histone deacetylases (HDACs) is one of important PTMs for epigenetic control, protein activity and protein stability. The regulation of acetylation of the N-terminal histone tails of core histone affects gene expression. Two class I HDAC genes and two class II HDAC genes have been identified in the Magnaporthe oryzae genome. Treatment with Rpd3/Hda1 family (classical) HDAC inhibitor inhibited the appressorium differentiation of M. oryzae. Treatment with trichostatin A, a classical HDAC inhibitor, also decreased pathogenesis. Furthermore, analyses of HDAC mutants indicated that MoHda1 and MoHos2 were required for vegetative growth and conidiation, and MoHos2 was required for appressorium formation. Disruption MoRPD3 was unsuccessful, as in the case with Aspergillus nidulans RpdA. These data indicated that HDACs have important roles in the asexual differentiation of M. oryzae. PMID:20118613

Izawa, Masumi; Takekawa, Osamu; Arie, Tsutomu; Teraoka, Tohru; Yoshida, Minoru; Kimura, Makoto; Kamakura, Takashi

2009-12-01

169

Histone deacetylase 3 is required for maintenance of bone mass during aging  

PubMed Central

Histone deacetylase 3 (Hdac3) is a nuclear enzyme that removes acetyl groups from lysine residues in histones and other proteins to epigenetically regulate gene expression. Hdac3 interacts with bone-related transcription factors and co-factors such as Runx2 and Zfp521, and thus is poised to play a key role in the skeletal system. To understand the role of Hdac3 in osteoblasts and osteocytes, Hdac3 conditional knockout (CKO) mice were created with the Osteocalcin (OCN) promoter driving Cre expression. Hdac3 CKOOCN mice were of normal size and weight, but progressively lost trabecular and cortical bone mass with age. The Hdac3 CKOOCN mice exhibited reduced cortical bone mineralization and material properties and suffered frequent fractures. Bone resorption was lower, not higher, in the Hdac3 CKOOCN mice, suggesting that primary defects in osteoblasts caused the reduced bone mass. Indeed, reductions in bone formation were observed. Osteoblasts and osteocytes from Hdac3 CKOOCN mice showed increased DNA damage and reduced functional activity in vivo and in vitro. Thus, Hdac3 expression in osteoblasts and osteocytes is essential for bone maintenance during aging. PMID:23085085

McGee-Lawrence, Meghan E.; Bradley, Elizabeth W.; Dudakovic, Amel; Carlson, Samuel W.; Ryan, Zachary C.; Kumar, Rajiv; Dadsetan, Mahrokh; Yaszemski, Michael J.; Chen, Qingshan; An, Kai-Nan; Westendorf, Jennifer J.

2012-01-01

170

Mammalian DNA repair: HATs and HDACs make their mark through histone acetylation.  

PubMed

Genetic information is recorded in specific DNA sequences that must be protected to preserve normal cellular function. Genome maintenance pathways have evolved to sense and repair DNA damage. Importantly, deleterious mutations that occur from mis-repaired lesions can lead to diseases such as cancer. As eukaryotic DNA is bound by histone proteins and organized into chromatin, the true in vivo substrate of transcription, replication and DNA repair is chromatin. Almost 50 years ago, it was found that histones contained the post-translational modification (PTM), acetylation. With the cloning and identification of transcription associated histone acetyltransferase (HAT) and histone deacetylase (HDAC) enzymes that write and erase the histone acetylation mark respectively, it was realized that this histone modification could be dynamically regulated. Chromatin is subjected to numerous PTMs that regulate chromatin structure and function, including DNA repair. As different organisms contain different histone modifications, chromatin-associated proteins and chromatin states, it is likely that chromatin-templated processes such as DNA repair will exhibit organismal differences. This article focuses on the DNA damage response (DDR) in mammalian cells and how the concerted activities of HAT and HDAC enzymes, and their histone acetylation targets, specifically participate in DNA double-strand break (DSB) repair. Defects in DNA repair and chromatin pathways are observed in cancer, and these pathways represent cancer therapeutic targets. Therefore, understanding the relationship between DNA repair and histone acetylations is important for providing mechanistic details of DSB repair within chromatin that has the potential to be exploited in the clinic. PMID:23927873

Gong, Fade; Miller, Kyle M

2013-10-01

171

Proteomic identification and functional characterization of MYH9, Hsc70, and DNAJA1 as novel substrates of HDAC6 deacetylase activity.  

PubMed

Histone deacetylase 6 (HDAC6), a predominantly cytoplasmic protein deacetylase, participates in a wide range of cellular processes through its deacetylase activity. However, the diverse functions of HDAC6 cannot be fully elucidated with its known substrates. In an attempt to explore the substrate diversity of HDAC6, we performed quantitative proteomic analyses to monitor changes in the abundance of protein lysine acetylation in response to HDAC6 deficiency. We identified 107 proteins with elevated acetylation in the liver of HDAC6 knockout mice. Three cytoplasmic proteins, including myosin heavy chain 9 (MYH9), heat shock cognate protein 70 (Hsc70), and dnaJ homolog subfamily A member 1 (DNAJA1), were verified to interact with HDAC6. The acetylation levels of these proteins were negatively regulated by HDAC6 both in the mouse liver and in cultured cells. Functional studies reveal that HDAC6-mediated deacetylation modulates the actin-binding ability of MYH9 and the interaction between Hsc70 and DNAJA1. These findings consolidate the notion that HDAC6 serves as a critical regulator of protein acetylation with the capability of coordinating various cellular functions. PMID:25311840

Zhang, Linlin; Liu, Shanshan; Liu, Ningning; Zhang, Yong; Liu, Min; Li, Dengwen; Seto, Edward; Yao, Tso-Pang; Shui, Wenqing; Zhou, Jun

2015-01-01

172

Neuroprotection by Histone Deacetylase-Related Protein  

Microsoft Academic Search

The expression of histone deacetylase-related protein (HDRP) is reduced in neurons undergoing apoptosis. Forced reduction of HDRP expression in healthy neurons by treatment with antisense oligonucleotides also induces cell death. Likewise, neurons cultured from mice lacking HDRP are more vulnerable to cell death. Adenovirally mediated expression of HDRP prevents neuronal death, showing that HDRP is a neuroprotective protein. Neuroprotection by

Brad E. Morrison; Nazanin Majdzadeh; Xiaoguang Zhang; Aaron Lyles; Rhonda Bassel-Duby; Eric N. Olson; Santosh R. D'Mello

2006-01-01

173

Deletion of Histone Deacetylase 7 in Osteoclasts Decreases Bone Mass in Mice by Interactions with MITF  

PubMed Central

Molecular regulators of osteoclast formation and function are an important area of research due to the central role of osteoclasts in bone resorption. Transcription factors such as MITF are essential for osteoclast generation by regulating expression of the genes required for cellular differentiation and resorptive function. We recently reported that histone deacetylase 7 (HDAC7) binds to and represses the transcriptional activity of MITF in osteoclasts, and that loss of HDAC7 in vitro accelerated osteoclastogenesis. In the current study, we extend this initial observation by showing that conditional deletion of HDAC7 in osteoclasts of mice leads to an in vivo enhancement in osteoclast formation, associated with increased bone resorption and lower bone mass. Expression of multiple MITF target genes is increased in bone marrow derived osteoclast cultures from the HDAC7 knockout mice. Interestingly, multiple regions of the HDAC7 amino-terminus can bind to MITF or exert repressive activity. Moreover, mutation or deletion of the HDAC7 conserved deacetylase catalytic domain had little effect on repressive function. These observations identify HDAC7 in osteoclasts as an important molecular regulator of MITF activity and bone homeostasis, but also highlight a gap in our understanding of exactly how HDAC7 functions as a corepressor. PMID:25875108

Stemig, Melissa; Astelford, Kristina; Emery, Ann; Cho, Jangyeun J.; Allen, Ben; Huang, Tsang-hai; Gopalakrishnan, Rajaram; Mansky, Kim C.; Jensen, Eric D.

2015-01-01

174

Specific targeting and constitutive association of histone deacetylase complexes during transcriptional repression.  

PubMed

Specific recruitment of corepressor complexes containing histone deacetylases (HDAC) by transcription factors is believed to play an essential role in transcriptional repression. Recent studies indicate that repression by unliganded nuclear hormone receptors and by the Mad family of repressors requires distinct HDAC-containing corepressor complexes. In this work, we show that unliganded TR specifically recruits only the closely related N-CoR and SMRT-HDAC3 complexes, whereas the Mad1 recruits only the Sin3-HDAC1/2 complex. Significantly, both the Sin3 and Mi-2/NURD complexes also exhibit constitutive association with chromatin and contribute to chromatin deacetylation in a nontargeted fashion. These results suggest that HDAC complexes can contribute to gene repression by two distinct mechanisms as follows: (1) specific targeting by repressors and (2) constitutive association with chromatin. PMID:11914274

Li, Jiwen; Lin, Qiushi; Wang, Weidong; Wade, Paul; Wong, Jiemin

2002-03-15

175

Global Histone H4 Acetylation and HDAC2 Expression in Colon Adenoma and Carcinoma  

PubMed Central

Chromatin remodeling and activation of transcription are important aspects of gene regulation, but these often go awry in disease progression, including during colon cancer development. We investigated the status of global histone acetylation (by measuring H3, H4 acetylation of lysine residues, which also occur over large regions of chromatin including coding regions and non-promoter sequences) and expression of histone deacetylase 2 (HDAC2) in colorectal cancer (CRC) tissue microarrays using immunohistochemical staining. Specifically, HDAC2 and the acetylation of histones H4K12 and H3K18 were evaluated in 134 colonic adenomas, 55 moderate to well differentiated carcinomas, and 4 poorly differentiated carcinomas compared to matched normal tissue. In addition, the correlation between expression of these epigenetic biomarkers and various clinicopathological factors including, age, location, and stage of the disease were analyzed. HDAC2 nuclear expression was detected at high levels in 81.9%, 62.1%, and 53.1% of CRC, adenomas, and normal tissue, respectively (P = 0.002). The corresponding nuclear global expression levels in moderate to well differentiated tumors for H4K12 and H3K18 acetylation were increased while these levels were decreased in poorly differentiated tumors (P = 0.02). HDAC2 expression was correlated significantly with progression of adenoma to carcinoma (P = 0.002), with a discriminative power of 0.74, when comparing cancer and non-cancer cases. These results suggest HDAC2 expression is significantly associated with CRC progression. PMID:19057998

Ashktorab, Hassan; Belgrave, Kevin; Hosseinkhah, Fatemeh; Brim, Hassan; Nouraie, Mehdi; Takkikto, Mikiko; Hewitt, Steve; Lee, Edward L.; Dashwood, R. H.; Smoot, Duane

2009-01-01

176

Histone deacetylase inhibitors SAHA and sodium butyrate block G1toS cell cycle progression in neurosphere formation by adult subventricular cells  

Microsoft Academic Search

Background  Histone deacetylases (HDACs) are enzymes that modulate gene expression and cellular processes by deacetylating histones and\\u000a non-histone proteins. While small molecule inhibitors of HDAC activity (HDACi) are used clinically in the treatment of cancer,\\u000a pre-clinical treatment models suggest they also exert neuroprotective effects and stimulate neurogenesis in neuropathological\\u000a conditions. However, the direct effects of HDACi on cell cycle progression and

Qiong Zhou; Clifton L Dalgard; Christopher Wynder; Martin L Doughty

2011-01-01

177

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

PubMed Central

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

2013-01-01

178

Highly ligand efficient and selective N-2-(Thioethyl)picolinamide histone deacetylase inhibitors inspired by the natural product psammaplin?A.  

PubMed

Novel picolinamide-based histone deacetylase (HDAC) inhibitors were developed, drawing inspiration from the natural product psammaplin?A. We found that the HDAC potency and isoform selectivity provided by the oxime unit of psammaplin?A could be reproduced by using carefully chosen heterocyclic frameworks. The resulting (hetero)aromatic amide based compounds displayed very high potency and isoform selectivity among the HDAC family, in addition to excellent ligand efficiency relative to previously reported HDAC inhibitors. In particular, the high HDAC1 isoform selectivity provided by the chloropyridine motif represents a valuable design criterion for the development of new lead compounds and chemical probes that target HDAC1. PMID:23184734

Baud, Matthias G J; Haus, Patricia; Leiser, Thomas; Meyer-Almes, Franz-Josef; Fuchter, Matthew J

2013-01-01

179

Histone Deacetylase Inhibitors Stimulate Histone H3 Lysine 4 Methylation in Part Via Transcriptional Repression of Histone H3 Lysine 4 DemethylasesS?  

PubMed Central

This study investigates the mechanism by which histone deacetylase (HDAC) inhibitors up-regulate histone H3 lysine 4 (H3K4) methylation. Exposure of LNCaP prostate cancer cells and the prostate tissue of transgenic adenocarcinoma of the mouse prostate mice to the pan- and class I HDAC inhibitors (S)-(+)-N-hydroxy-4-(3-methyl-2-phenyl-butyrylamino)-benzamide (AR42), N-(2-aminophenyl)-4-[N-(pyridine-3-yl-methoxycarbonyl)-aminomethyl]-benzamide (MS-275), and vorinostat led to differential increases in H3K4 methylation. Chromatin immunoprecipitation shows that this accumulation of methylated H3K4 occurred in conjunction with decreases in the amount of the H3K4 demethylase RBP2 at the promoter of genes associated with tumor suppression and differentiation, including KLF4 and E-cadherin. This finding, together with the HDAC inhibitor-induced up-regulation of KLF4 and E-cadherin, suggests that HDAC inhibitors could activate the expression of these genes through changes in histone methylation status. Evidence indicates that this up-regulation of H3K4 methylation was attributable to the suppressive effect of these HDAC inhibitors on the expression of RBP2 and other JARID1 family histone demethylases, including PLU-1, SMCX, and LSD1, via the down-regulation of Sp1 expression. Moreover, shRNA-mediated silencing of the class I HDAC isozymes 1, 2, 3, and 8, but not that of the class II isozyme HDAC6, mimicked the drug effects on H3K4 methylation and H3K4 demethylases, which could be reversed by ectopic Sp1 expression. These data suggest a cross-talk mechanism between HDACs and H3K4 demethylases via Sp1-mediated transcriptional regulation, which underlies the complexity of the functional role of HDACs in the regulation of histone modifications. PMID:20959362

Huang, Po-Hsien; Chen, Chun-Han; Chou, Chih-Chien; Sargeant, Aaron M.; Kulp, Samuel K.; Teng, Che-Ming; Byrd, John C.

2011-01-01

180

Sensing of ionizing radiation-induced DNA damage by ATM through interaction with histone deacetylase.  

PubMed

The ATM gene is mutated in individuals with ataxia telangiectasia, a human genetic disease characterized by extreme sensitivity to radiation. The ATM protein acts as a sensor of radiation-induced cellular damage and contributes to cell cycle regulation, signal transduction, and DNA repair; however, the mechanisms underlying these functions of ATM remain largely unknown. Binding and immunoprecipitation assays have now shown that ATM interacts with the histone deacetylase HDAC1 both in vitro and in vivo, and that the extent of this association is increased after exposure of MRC5CV1 human fibroblasts to ionizing radiation. Histone deacetylase activity was also detected in immunoprecipitates prepared from these cells with antibodies to ATM, and this activity was blocked by the histone deacetylase inhibitor trichostatin A. These results suggest a previously unanticipated role for ATM in the modification of chromatin components in response to ionizing radiation. PMID:10531300

Kim, G D; Choi, Y H; Dimtchev, A; Jeong, S J; Dritschilo, A; Jung, M

1999-10-29

181

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

182

In Vitro Targeting Reveals Intrinsic Histone Tail Specificity of the Sin3/Histone Deacetylase and N-CoR/SMRT Corepressor Complexes  

PubMed Central

The histone code is among others established via differential acetylation catalyzed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). To unambiguously determine the histone tail specificity of HDAC-containing complexes, we have established an in vitro system consisting of nucleosomal templates reconstituted with hyperacetylated histones or recombinant histones followed by acetylation with native SAGA or NuA4. Selective targeting of the mammalian Sin3/HDAC and N-CoR/SMRT corepressor complexes by using specific chimeric repressors created a near physiological setting to assess their histone tail specificity. Recruitment of the Sin3/HDAC complex to nucleosomal templates preacetylated with SAGA or NuA4 resulted in deacetylation of histones H3 and H4, whereas recruitment of N-CoR/SMRT resulted in deacetylation of histone H3 only. These results provide solid evidence that HDAC-containing complexes display distinct, intrinsic histone tail specificities and hence may function differently to regulate chromatin structure and transcription. PMID:14993276

Vermeulen, Michiel; Carrozza, Michael J.; Lasonder, Edwin; Workman, Jerry L.; Logie, Colin; Stunnenberg, Hendrik G.

2004-01-01

183

Phenylhexyl isothiocyanate has dual function as histone deacetylase inhibitor and hypomethylating agent and can inhibit myeloma cell growth by targeting critical pathways  

Microsoft Academic Search

Histone deacetylase (HDAC) inhibitors are a new class of chemotherapeutic agents. Our laboratory has recently reported that phenylhexyl isothiocyanate (PHI), a synthetic isothiocyanate, is an inhibitor of HDAC. In this study we examined whether PHI is a hypomethylating agent and its effects on myeloma cells. RPMI8226, a myeloma cell line, was treated with PHI. PHI inhibited the proliferation of the

Quanyi Lu; Xianghua Lin; Jean Feng; Xiangmin Zhao; Ruth Gallagher; Marietta Y Lee; Jen-Wei Chiao; Delong Liu

2008-01-01

184

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

185

Histone deacetylase inhibitors for treatment of hepatocellular carcinoma.  

PubMed

Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. Surgical resection has been considered the optimal treatment approach, but only a small proportion of patients are suitable candidates for surgery, and the relapse rate is high. Approaches to prevent recurrence, including chemoembolization before and adjuvant therapy after surgery, have proven to have a limited benefit; liver transplantation is successful in treating limited-stage HCC because only a minority of patients qualify for transplantation. Therefore, new therapeutic strategies are urgently needed. Because in addition to the classical genetic mechanisms of deletion or inactivating point mutations, epigenetic alterations, such as hyperacetylation of the chromatin-associated histones (responsible for gene silencing), are believed to be involved in the development and progression of HCC, novel compounds endowed with a histone deacetylase (HDAC) inhibitory activity are an attractive therapeutic approach. In particular, pre-clinical results obtained using HA-But, an HDAC inhibitor in which butyric acid residues are esterified to a hyaluronic acid backbone and characterized by a high affinity for the membrane receptor CD44, indicated that this class of compounds may represent a promising approach for hepatocellular carcinoma treatment. PMID:16115366

Coradini, Danila; Speranza, Annalisa

2005-09-01

186

Monoubiquitination of Filamin B Regulates Vascular Endothelial Growth Factor-Mediated Trafficking of Histone Deacetylase 7  

PubMed Central

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

2013-01-01

187

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

188

Identification of Components of the Murine Histone Deacetylase 6 Complex: Link between Acetylation and Ubiquitination Signaling Pathways  

Microsoft Academic Search

The immunopurification of the endogenous cytoplasmic murine histone deacetylase 6 (mHDAC6), a member of the class II HDACs, from mouse testis cytosolic extracts allowed the identification of two associated proteins. Both were mammalian homologues of yeast proteins known to interact with each other and involved in the ubiquitin signaling pathway: p97\\/VCP\\/Cdc48p, a homologue of yeast Cdc48p, and phospholipase A2-activating protein,

D. Seigneurin-Berny; A. Verdel; S. Curtet; C. Lemercier; J. Garin; S. Rousseaux; S. Khochbin

2001-01-01

189

Histone deacetylase activity is essential for the expression of HoxA9 and for endothelial commitment of progenitor cells  

Microsoft Academic Search

The regulation of acetylation is central for the epigenetic control of lineage-specific gene expression and determines cell fate decisions. We provide evidence that the inhibition of histone deacetylases (HDACs) blocks the endothelial differentiation of adult progenitor cells. To define the mechanisms by which HDAC inhibition prevents endothelial differentiation, we determined the expression of homeobox transcription factors and demonstrated that HoxA9

Lothar Rössig; Carmen Urbich; Thomas Brühl; Elisabeth Dernbach; Christopher Heeschen; Emmanouil Chavakis; Ken-ichiro Sasaki; Diana Aicher; Florian Diehl; Florian Seeger; Michael Potente; Alexandra Aicher; Lucia Zanetta; Elisabetta Dejana; Andreas M. Zeiher; Stefanie Dimmeler

190

Dual Targeting of Histone Deacetylase and Topoisomerase II with Novel Bifunctional Inhibitors  

PubMed Central

Strategies to ameliorate the flaws of current chemotherapeutic agents, while maintaining potent anticancer activity, are of particular interest. Agents which can modulate multiple targets may have superior utility and fewer side effects than current single-target drugs. To explore the prospect in cancer therapy of a bivalent agent that combines two complimentary chemo-active groups within a single molecular architecture; we have synthesized dual-acting histone deacetylase and topoisomerase II inhibitors. These dual-acting agents are derived from suberoylanilide hydroxamic acid (SAHA) and anthracycline daunorubicin; prototypical histone deacetylase (HDAC) and topoisomerase II (Topo II) inhibitors respectively. We report herein that these agents present the signatures of inhibition of HDAC and Topo II in both cell-free and whole cell assays. Moreover, these agents potently inhibit the proliferation of representative cancer cell lines. PMID:22260166

Guerrant, William; Patil, Vishal; Canzoneri, Joshua C.; Oyelere, Adegboyega K.

2012-01-01

191

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

192

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 5 hours) in vivo. MPT0E014 (1 ?M)-treated PV cardiomyocytes (n=12) had slower beating rates (2.1 ± 0.2 vs. 2.8 ± 0.1 Hz, 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 ± 0.3 Hz). MS-275-treated PV cardiomyocytes (n = 12, 2.3 ± 0.2 Hz), but not MC-1568-treated PV cardiomyocytes (n=14, 3.1 ± 0.3 Hz) 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

2014-12-20

193

Histone deacetylase inhibitors in glioblastoma: pre-clinical and clinical experience.  

PubMed

Epigenetic mechanisms are increasingly recognized as a major factor contributing to pathogenesis of cancer including glioblastoma, the most common and most malignant primary brain tumour in adults. Enzymatic modifications of histone proteins regulating gene expression are being exploited for therapeutic drug targeting. Over the last decade, numerous studies have shown promising results with histone deacetylase (HDAC) inhibitors in various malignancies. This article provides a brief overview of mechanism of anti-cancer effect and pharmacology of HDAC inhibitors and summarizes results from pre-clinical and clinical studies in glioblastoma. It analyses experience with HDAC inhibitors as single agents as well as in combination with targeted agents, cytotoxic chemotherapy and radiotherapy. Hallmark features of glioblastoma, such as uncontrolled cellular proliferation, invasion, angiogenesis and resistance to apoptosis, have been shown to be targeted by HDAC inhibitors in experiments with glioblastoma cell lines. Vorinostat is the most advanced HDAC inhibitor that entered clinical trials in glioblastoma, showing activity in recurrent disease. Multiple phase II trials with vorinostat in combination with targeted agents, temozolomide and radiotherapy are currently recruiting. While the results from pre-clinical studies are encouraging, early clinical trials showed only modest benefit and the value of HDAC inhibitors for clinical practice will need to be confirmed in larger prospective trials. Further research in epigenetic mechanisms driving glioblastoma pathogenesis and identification of molecular subtypes of glioblastoma is needed. This will hopefully lead to better selection of patients who will benefit from treatment with HDAC inhibitors. PMID:24838514

Bezecny, Pavel

2014-06-01

194

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

195

Histone Deacetylase Inhibitor, Trichostatin A, Affects Gene Expression Patterns during Morphogenesis of Chicken Limb Buds in vivo  

Microsoft Academic Search

Acetylation is one of the key chromatin modifications that control gene transcription during embryonic development and tumorigenesis. The types of genes sensitive to such modifications in vivo are not known to date. We investigated the expression of a number of genes involved in embryonic development after treatment with trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, in the limbs of

Wanghong Zhao; Fangping Dai; Alexander Bonafede; Stefan Schäfer; Manfred Jung; Faisal Yusuf; Anton J. Gamel; Jianlin Wang; Beate Brand-Saberi

2009-01-01

196

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

197

The interplay between microRNAs and histone deacetylases in neurological diseases.  

PubMed

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

2014-11-01

198

Kinetic method for the large-scale analysis of the binding mechanism of histone deacetylase inhibitors.  

PubMed

Performing kinetic studies on protein ligand interactions provides important information on complex formation and dissociation. Beside kinetic parameters such as association rates and residence times, kinetic experiments also reveal insights into reaction mechanisms. Exploiting intrinsic tryptophan fluorescence a parallelized high-throughput Förster resonance energy transfer (FRET)-based reporter displacement assay with very low protein consumption was developed to enable the large-scale kinetic characterization of the binding of ligands to recombinant human histone deacetylases (HDACs) and a bacterial histone deacetylase-like amidohydrolase (HDAH) from Bordetella/Alcaligenes. For the binding of trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA), and two other SAHA derivatives to HDAH, two different modes of action, simple one-step binding and a two-step mechanism comprising initial binding and induced fit, were verified. In contrast to HDAH, all compounds bound to human HDAC1, HDAC6, and HDAC8 through a two-step mechanism. A quantitative view on the inhibitor-HDAC systems revealed two types of interaction, fast binding and slow dissociation. We provide arguments for the thesis that the relationship between quantitative kinetic and mechanistic information and chemical structures of compounds will serve as a valuable tool for drug optimization. PMID:24882269

Meyners, Christian; Baud, Matthias G J; Fuchter, Matthew J; Meyer-Almes, Franz-Josef

2014-09-01

199

Thermodynamics of ligand binding to histone deacetylase like amidohydrolase from Bordetella/Alcaligenes.  

PubMed

Thermodynamic studies on ligand-protein binding have become increasingly important in the process of drug design. In combination with structural data and molecular dynamics simulations, thermodynamic studies provide relevant information about the mode of interaction between compounds and their target proteins and therefore build a sound basis for further drug optimization. Using the example of histone deacetylases (HDACs), particularly the histone deacetylase like amidohydrolase (HDAH) from Bordetella/Alcaligenes, a novel sensitive competitive fluorescence resonance energy transfer-based binding assay was developed and the thermodynamics of interaction of both fluorescent ligands and inhibitors to histone deacetylase like amidohydrolase were investigated. The assay consumes only small amounts of valuable target proteins and is suitable for fast kinetic and mechanistic studies as well as high throughput screening applications. Binding affinity increased with increasing length of aliphatic spacers (n = 4-7) between the hydroxamate moiety and the dansyl head group of ligand probes. Van't Hoff plots revealed an optimum in enthalpy contribution to the free energy of binding for the dansyl-ligand with hexyl spacer. The selectivity in the series of dansyl-ligands against human class I HDAC1 but not class II HDACs 4 and 6 increased with the ratio of ?H(0)/?G(0). The data clearly emphasize the importance of thermodynamic signatures as useful general guidance for the optimization of ligands or rational drug design. PMID:24446380

Meyners, Christian; Baud, Matthias G J; Fuchter, Matthew J; Meyer-Almes, Franz-Josef

2014-03-01

200

Epigenetic influences on sensory regeneration: histone deacetylases regulate supporting cell proliferation in the avian utricle.  

PubMed

The sensory hair cells of the cochlea and vestibular organs are essential for normal hearing and balance function. The mammalian ear possesses a very limited ability to regenerate hair cells and their loss can lead to permanent sensory impairment. In contrast, hair cells in the avian ear are quickly regenerated after acoustic trauma or ototoxic injury. The very different regenerative abilities of the avian vs. mammalian ear can be attributed to differences in injury-evoked expression of genes that either promote or inhibit the production of new hair cells. Gene expression is regulated both by the binding of cis-regulatory molecules to promoter regions as well as through structural modifications of chromatin (e.g., methylation and acetylation). This study examined effects of histone deacetylases (HDACs), whose main function is to modify histone acetylation, on the regulation of regenerative proliferation in the chick utricle. Cultures of regenerating utricles and dissociated cells from the utricular sensory epithelia were treated with the HDAC inhibitors valproic acid, trichostatin A, sodium butyrate, and MS-275. All of these molecules prevent the enzymatic removal of acetyl groups from histones, thus maintaining nuclear chromatin in a "relaxed" (open) configuration. Treatment with all inhibitors resulted in comparable decreases in supporting cell proliferation. We also observed that treatment with the HDAC1-, 2-, and 3-specific inhibitor MS-275 was sufficient to reduce proliferation and that two class I HDACs--HDAC1 and HDAC2--were expressed in the sensory epithelium of the utricle. These results suggest that inhibition of specific type I HDACs is sufficient to prevent cell cycle entry in supporting cells. Notably, treatment with HDAC inhibitors did not affect the differentiation of replacement hair cells. We conclude that histone deacetylation is a positive regulator of regenerative proliferation but is not critical for avian hair cell differentiation. PMID:19340485

Slattery, Eric L; Speck, Judith D; Warchol, Mark E

2009-09-01

201

Activation of insulin-like growth factor receptor signaling mediates resistance to histone deacetylase inhibitors.  

PubMed

Histone deacetylases (HDACs) are considered promising targets in the treatment of hematologic malignancies and several types of solid tumors, including non-small cell lung cancer (NSCLC). However, the efficacy of HDAC inhibitors in solid tumors is marginal, and the mechanisms underlying resistance to HDAC inhibitors are largely unknown. Here, we demonstrate the involvement of type 1 insulin-like growth factor receptor (IGF-1R) signaling in resistance to HDAC inhibitors in NSCLC. Using MTT and soft-agar colony formation assays, we selected NSCLC cell lines that exhibited intrinsic resistance to vorinostat. Treatment with vorinostat activated IGF-1R signaling in vorinostat-resistant but not vorinostat-sensitive NSCLC cells. Other HDAC inhibitors, including trichostatin A, sodium butyrate, and depsipeptide, also activated IGF-1R signaling in vorinostat-resistant NSCLC cells. Blockade of IGF-1R signaling via IGF-1R monoclonal antibodies (mAbs) or through knockdown of IGF-1R via RNA interference sensitized vorinostat-resistant cells to HDAC inhibition. Finally, IGF-1R mAbs sensitized xenograft tumors of vorinostat-resistant cells to vorinostat treatment in vivo. These findings suggest that IGF-1R activation is generally involved in resistance to HDAC inhibitors and that targeting IGF-1R is an effective strategy for overcoming resistance to HDAC inhibitors in NSCLC. PMID:25721083

Kim, Jin-Soo; Lee, Su-Chan; Min, Hye-Young; Park, Kwan Hee; Hyun, Seung Yeob; Kwon, So Jung; Choi, Sun Phil; Kim, Woo-Young; Lee, Hyo-Jong; Lee, Ho-Young

2015-06-01

202

A Histone Deacetylase 4/Myogenin Positive Feedback Loop Coordinates Denervation-dependent Gene Induction and Suppression  

PubMed Central

Muscle activity contributes to formation of the neuromuscular junction and affects muscle metabolism and contractile properties through regulated gene expression. However, the mechanisms coordinating these diverse activity-regulated processes remain poorly characterized. Recently, it was reported that histone deacetylase 4 (HDAC4) can mediate denervation-induced myogenin and nicotinic acetylcholine receptor gene expression. Here, we report that HDAC4 is not only necessary for denervation-dependent induction of genes involved in synaptogenesis (nicotinic acetylcholine receptor and muscle-specific receptor tyrosine kinase) but also for denervation-dependent suppression of genes involved in glycolysis (muscle-specific enolase and phosphofructokinase). In addition, HDAC4 differentially regulates genes involved in muscle fiber type specification by inducing myosin heavy chain IIA and suppressing myosin heavy chain IIB. Consistent with these regulated gene profiles, HDAC4 is enriched in fast oxidative fibers of innervated tibialis anterior muscle and HDAC4 knockdown enhances glycolysis in cultured myotubes. HDAC4 mediates gene induction indirectly by suppressing the expression of Dach2 and MITR that function as myogenin gene corepressors. In contrast, HDAC4 is directly recruited to myocyte enhancer factor 2 sites within target promoters to mediate gene suppression. Finally, we discovered an HDAC4/myogenin positive feedback loop that coordinates gene induction and repression underlying muscle phenotypic changes after muscle denervation. PMID:19109424

Tang, Huibin; Macpherson, Peter; Marvin, Michael; Meadows, Eric; Klein, William H.; Yang, Xiang-Jiao

2009-01-01

203

Glycolysis-dependent histone deacetylase 4 degradation regulates inflammatory cytokine production  

PubMed Central

Activation of the inflammatory response is accompanied by a metabolic shift to aerobic glycolysis. Here we identify histone deacetylase 4 (HDAC4) as a new component of the immunometabolic program. We show that HDAC4 is required for efficient inflammatory cytokine production activated by lipopolysaccharide (LPS). Surprisingly, prolonged LPS treatment leads to HDAC4 degradation. LPS-induced HDAC4 degradation requires active glycolysis controlled by GSK3? and inducible nitric oxide synthase (iNOS). Inhibition of GSK3? or iNOS suppresses nitric oxide (NO) production, glycolysis, and HDAC4 degradation. We present evidence that sustained glycolysis induced by LPS treatment activates caspase-3, which cleaves HDAC4 and triggers its degradation. Of importance, a caspase-3–resistant mutant HDAC4 escapes LPS-induced degradation and prolongs inflammatory cytokine production. Our findings identify the GSK3?-iNOS-NO axis as a critical signaling cascade that couples inflammation to metabolic reprogramming and a glycolysis-driven negative feedback mechanism that limits inflammatory response by triggering HDAC4 degradation. PMID:25187650

Wang, Bin; Liu, Ting-yu; Lai, Chun-Hsiang; Rao, Yan-hua; Choi, Moon-Chang; Chi, Jen-Tsan; Dai, Jian-wu; Rathmell, Jeffrey C.; Yao, Tso-Pang

2014-01-01

204

Histone deacetylases inhibition and tumor cells cytotoxicity by CNS-active VPA constitutional isomers and derivatives.  

PubMed

The tumor cells toxicity of the antiepileptic drug valproic acid (VPA) has been associated with the inhibition of histone deacetylases (HDACs). We have assessed, in comparison to VPA, the HDACs inhibition and tumor cells cytotoxicities of CNS-active VPA's constitutional isomers, valnoctic acid (VCA), propylisopropylacetic acid (PIA), diisopropylacetic acid (DIA), VPA's cyclopropyl analogue 2,2,3,3-tetramethylcyclopropanecarboxylic acid (TMCA) and VPA's metabolites, 2-ene-VPA and 4-ene-VPA, all possessing, as does VPA, eight carbon atoms in their structures. The aim was to define structural components of the VPA molecule that are involved in HDACs inhibition and tumor cells cytotoxicity. HDACs inhibition by the above-mentioned compounds was estimated using an acetylated lysine substrate and HeLa nuclear extract as a HDACs source. SW620 cells were used for assessing HDACs inhibition in vivo. The cytotoxicity of these compounds was assessed in SW620 and 1106mel cells. HDAC inhibition potency was the highest for VPA and 4-ene-VPA (IC(50)=1.5mM each). 2-Ene-VPA inhibited HDACs with IC(50)=2.8mM. IC(50) values of the other tested compounds for HDACs inhibition were higher than 5mM, 4-ene-VPA and VPA induced histone hyperacetylation in SW620 cells. 4-Ene-VPA and VPA at 2mM each were also most potent in reducing cell viability, to 59+/-2.0% and 67.3+/-5.4%, respectively, compared to control. VCA, PIA, DIA, TMCA, 2-ene-VPA and valpromide (VPD) did not reduce viability to less than 80%. All tested compounds did not significantly affect the cell cycle of SW620 cells. In conclusion, in comparison to the VPA derivatives and constitutional isomers tested in this study, VPA had the optimal chemical structure in terms of HDACs inhibition and tumor cells cytotoxicity. PMID:15857614

Eyal, Sara; Yagen, Boris; Shimshoni, Jakob; Bialer, Meir

2005-05-15

205

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

206

Recruitment of Histone Deacetylase 3 to the Interferon-A Gene Promoters Attenuates Interferon Expression  

PubMed Central

Background Induction of Type I Interferon (IFN) genes constitutes an essential step leading to innate immune responses during virus infection. Sendai virus (SeV) infection of B lymphoid Namalwa cells transiently induces the transcriptional expression of multiple IFN-A genes. Although transcriptional activation of IFN-A genes has been extensively studied, the mechanism responsible for the attenuation of their expression remains to be determined. Principal Findings In this study, we demonstrate that virus infection of Namalwa cells induces transient recruitment of HDAC3 (histone deacetylase 3) to IFN-A promoters. Analysis of chromatin-protein association by Chip-QPCR demonstrated that recruitment of interferon regulatory factor (IRF)3 and IRF7, as well as TBP correlated with enhanced histone H3K9 and H3K14 acetylation, whereas recruitment of HDAC3 correlated with inhibition of histone H3K9/K14 acetylation, removal of IRF7 and TATA-binding protein (TBP) from IFN-A promoters and inhibition of virus-induced IFN-A gene transcription. Additionally, HDAC3 overexpression reduced, and HDAC3 depletion by siRNA enhanced IFN-A gene expression. Furthermore, activation of IRF7 enhanced histone H3K9/K14 acetylation and IFN-A gene expression, whereas activation of both IRF7 and IRF3 led to recruitment of HDAC3 to the IFN-A gene promoters, resulting in impaired histone H3K9 acetylation and attenuation of IFN-A gene transcription. Conclusion Altogether these data indicate that reversal of histone H3K9/K14 acetylation by HDAC3 is required for attenuation of IFN-A gene transcription during viral infection. PMID:22685561

Génin, Pierre; Lin, Rongtuan; Hiscott, John; Civas, Ahmet

2012-01-01

207

Histone deacetylase inhibitor apicidin downregulates DNA methyltransferase 1 expression and induces repressive histone modifications via recruitment of corepressor complex to promoter region in human cervix cancer cells  

Microsoft Academic Search

Dysregulation of DNA methyltransferase (DNMT)1 expression is associated with cellular transformation, and inhibition of DNMT1 exerts antitumorigenic effects. Here, we report that DNMT1 abnormally expressed in HeLa cells is downregulated by a histone deacetylase (HDAC) inhibitor apicidin, which is correlated with induction of repressive histone modifications on the promoter site. Apicidin selectively represses the expression of DNMT1 among DNMTs in

J S You; J K Kang; E K Lee; J C Lee; S H Lee; Y J Jeon; D H Koh; S H Ahn; D-W Seo; H Y Lee; E-J Cho; J-W Han

2008-01-01

208

Histone deacetylase inhibitor depsipeptide activates silenced genes through decreasing both CpG and H3K9 methylation on the promoter  

Microsoft Academic Search

Histone deacetylase inhibitor (HDACi) has been shown to demethylate the mammalian genome, which further strengthens the concept that DNA methylation and histone modifications interact in regulation of gene expression. Here, we report that an HDAC inhibitor, depsipeptide, exhibited significant demethylating activity on the promoters of several genes, including p16, SALL3, and GATA4 in human lung cancer cell lines H719 and

Li-Peng Wu; Xi Wang; Lian Li; Ying Zhao; Shaoli Lu; Yu Yu; W. Zhou; Xiangyu Liu; Jing Yang; Zhixin Zheng; Hui Zhang; Jingnan Feng; Yang Yang; Haiying Wang; Wei-Guo Zhu

2008-01-01

209

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

210

Human HDAC1 and HDAC2 function in the DNA-damage response to promote DNA nonhomologous end-joining  

Microsoft Academic Search

DNA double-strand break (DSB) repair occurs within chromatin and can be modulated by chromatin-modifying enzymes. Here we identify the related human histone deacetylases HDAC1 and HDAC2 as two participants in the DNA-damage response. We show that acetylation of histone H3 Lys56 (H3K56) was regulated by HDAC1 and HDAC2 and that HDAC1 and HDAC2 were rapidly recruited to DNA-damage sites to

Kyle M Miller; Jorrit V Tjeertes; Julia Coates; Gaëlle Legube; Sophie E Polo; Sébastien Britton; Stephen P Jackson

2010-01-01

211

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

212

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

213

The antiparasitic clioquinol induces apoptosis in leukemia and myeloma cells by inhibiting histone deacetylase activity.  

PubMed

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

2013-11-22

214

Inhibition of histone deacetylase in utero causes sociability deficits in postnatal mice.  

PubMed

Exposure to sodium valproate (VPA) in utero increases the risk of language impairment and a diagnosis of autism spectrum disorder (ASD). Mice exposed to VPA while in utero have also shown postnatal social deficits. Inhibition of histone deacetylase (HDAC) is one of VPA's many biological effects. The main objective of this study was to test the hypothesis that HDAC inhibition causes these behavioral outcomes following prenatal VPA exposure in mice. We exposed embryonic mice to VPA, the HDAC inhibitor trichostatin A (TSA), or vehicle controls. TSA (1mg/kg) inhibited HDAC in embryonic tissue at a level comparable to 600 mg/kg VPA, resulting in significant increases in histone H3 and H4 acetylation, and histone H3 lysine 4 tri-methylation. Postnatally, decreases in ultrasonic vocalization, olfactory motivation and sociability were observed in TSA and VPA-exposed pups. Treated mice exhibited elevated digging and grooming suggestive of mild restrictive and repetitive behaviors. Olfactory social preference, social novelty and habituation were normal. Together, these data indicate that embryonic HDAC inhibition alone can cause abnormal social behaviors in mice. This result serves as a molecular understanding of infant outcomes following mild VPA exposure in utero. PMID:24103642

Moldrich, Randal X; Leanage, Gayeshika; She, David; Dolan-Evans, Elliot; Nelson, Michael; Reza, Nargis; Reutens, David C

2013-11-15

215

Histone deacetylases 1 and 2 act in concert to promote the G1-to-S progression  

PubMed Central

Histone deacetylases (HDACs) regulate gene expression by deacetylating histones and also modulate the acetylation of a number of nonhistone proteins, thus impinging on various cellular processes. Here, we analyzed the major class I enzymes HDAC1 and HDAC2 in primary mouse fibroblasts and in the B-cell lineage. Fibroblasts lacking both enzymes fail to proliferate in culture and exhibit a strong cell cycle block in the G1 phase that is associated with up-regulation of the CDK inhibitors p21WAF1/CIP1 and p57Kip2 and of the corresponding mRNAs. This regulation is direct, as in wild-type cells HDAC1 and HDAC2 are bound to the promoter regions of the p21 and p57 genes. Furthermore, analysis of the transcriptome and of histone modifications in mutant cells demonstrated that HDAC1 and HDAC2 have only partly overlapping roles. Next, we eliminated HDAC1 and HDAC2 in the B cells of conditionally targeted mice. We found that B-cell development strictly requires the presence of at least one of these enzymes: When both enzymes are ablated, B-cell development is blocked at an early stage, and the rare remaining pre-B cells show a block in G1 accompanied by the induction of apoptosis. In contrast, elimination of HDAC1 and HDAC2 in mature resting B cells has no negative impact, unless these cells are induced to proliferate. These results indicate that HDAC1 and HDAC2, by normally repressing the expression of p21 and p57, regulate the G1-to-S-phase transition of the cell cycle. PMID:20194438

Yamaguchi, Teppei; Cubizolles, Fabien; Zhang, Yu; Reichert, Nina; Kohler, Hubertus; Seiser, Christian; Matthias, Patrick

2010-01-01

216

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

217

Down-Regulation of Deacetylase HDAC6 Inhibits the Melanoma Cell Line A375.S2 Growth through ROS-Dependent Mitochondrial Pathway  

PubMed Central

Previous studies have shown that histone deacetylase 6 (HDAC6) plays critical roles in many cellular processes related to cancer. However, its biological roles in the development of melanoma remain unexplored. Our aim was to investigate whether HDAC6 has a biological role in human melanoma development and to understand its underlying mechanism. In the present study, HDAC6 expression was up-regulated in melanoma tissues and cell lines. Knockdown of HDAC6 significantly inhibited the proliferation and colony formation ability of A375.S2 cells, promoted cell arrest at G0/G1 phase and apoptosis. Additionally, western blotting assay showed that HDAC6 silencing suppressed Bcl-2 level and enhanced Bax level, then activated caspase-9 and caspase-3, and further activated the release of cytochrome c from mitochondria to cytoplasm, finally induced cell apoptosis involving the mitochondrial pathway. Knockdown of HDAC6 triggered a significant generation of ROS and disruption of mitochondrial membrane potential (MMP). Furthermore, ROS inhibitor, NAC reduced HDAC6 siRNA-induced ROS production, and blocked HDAC6 siRNA-induced loss of MMP and apoptosis. NAC also significantly blocked HDAC6 siRNA-induced mtDNA copy number decrease and mitochondrial biogenesis and degradation imbalance. In conclusion, the results showed that knockdown of HDAC6 induced apoptosis in human melanoma A375.S2 cells through a ROS-dependent mitochondrial pathway. PMID:25774669

Bai, Jun; Lei, Yun; An, Gai-li; He, Li

2015-01-01

218

Histone deacetylase 8 is deregulated in urothelial cancer but not a target for efficient treatment  

PubMed Central

Background Previous studies have shown that class-I histone deacetylase (HDAC) 8 mRNA is upregulated in urothelial cancer tissues and urothelial cancer cell lines compared to benign controls. Using urothelial cancer cell lines we evaluated whether specific targeting of HDAC8 might be a therapeutic option in bladder cancer treatment. Methods We conducted siRNA-mediated knockdown and specific pharmacological inhibition of HDAC8 with the three different inhibitors compound 2, compound 5, and compound 6 in several urothelial carcinoma cell lines with distinct HDAC8 expression profiles. Levels of HDAC and marker proteins were determined by western blot analysis and mRNA levels were measured by quantitative real-time PCR. Cellular effects of HDAC8 suppression were analyzed by ATP assay, flow cytometry, colony forming assay and migration assay. Results Efficient siRNA-mediated knockdown of HDAC8 reduced proliferation up to 45%. The HDAC8 specific inhibitors compound 5 and compound 6 significantly reduced viability of all urothelial cancer cell lines (IC50 9 – 21 ?M). Flow cytometry revealed only a slight increase in the sub-G1 fraction indicating a limited induction of apoptosis. Expression of thymidylate synthase was partly reduced; PARP-cleavage was not detected. The influence of the pharmacological inhibition on clonogenic growth and migration show a cell line- and inhibitor-dependent reduction with the strongest effects after treatment with compound 5 and compound 6. Conclusions Deregulation of HDAC8 is frequent in urothelial cancer, but neither specific pharmacological inhibition nor siRNA-mediated knockdown of HDAC8 impaired viability of urothelial cancer cell lines in a therapeutic useful manner. Accordingly, HDAC8 on its own is not a promising drug target in bladder cancer. PMID:25011684

2014-01-01

219

Histone deacetylase 4 controls neointimal hyperplasia via stimulating proliferation and migration of vascular smooth muscle cells.  

PubMed

Histone deacetylases (HDACs) are transcriptional coregulators. Recently, we demonstrated that HDAC4, one of class IIa family members, promotes reactive oxygen species-dependent vascular smooth muscle inflammation and mediates development of hypertension in spontaneously hypertensive rats. Pathogenesis of hypertension is, in part, modulated by vascular structural remodeling via proliferation and migration of vascular smooth muscle cells (SMCs). Thus, we examined whether HDAC4 controls SMC proliferation and migration. In rat mesenteric arterial SMCs, small interfering RNA against HDAC4 inhibited platelet-derived growth factor (PDGF)-BB-induced SMC proliferation as determined by a cell counting and bromodeoxyuridine incorporation assay as well as migration as determined by Boyden chamber assay. Expression and activity of HDAC4 were increased by PDGF-BB. HDAC4 small interfering RNA inhibited phosphorylation of p38 mitogen-activated protein kinase and heat shock protein 27 and expression of cyclin D1 as measured by Western blotting. HDAC4 small interfering RNA also inhibited PDGF-BB-induced reactive oxygen species production as measured fluorometrically using 2', 7'-dichlorofluorescein diacetate and nicotinamide adenine dinucleotide phosphate oxidase activity as measured by lucigenin assay. A Ca(2+)/calmodulin-dependent protein kinase II inhibitor, KN93, inhibited PDGF-BB-induced SMC proliferation and migration as well as phosphorylation of HDAC4. In vivo, a class IIa HDACs inhibitor, MC1568 prevented neointimal hyperplasia in mice carotid ligation model. MC1568 also prevented increased activation of HDAC4 in the neointimal lesions. The present results for the first time demonstrate that HDAC4 controls PDGF-BB-induced SMC proliferation and migration through activation of p38 mitogen-activated protein kinase/heat shock protein 27 signals via reactive oxygen species generation in a Ca(2+)/calmodulin-dependent protein kinase-dependent manner, which may lead to the neointimal hyperplasia in vivo. PMID:24166750

Usui, Tatsuya; Morita, Tomoka; Okada, Muneyoshi; Yamawaki, Hideyuki

2014-02-01

220

Genomewide analysis of nucleosome density histone acetylation and HDAC function in fission yeast.  

PubMed

We have conducted a genomewide investigation into the enzymatic specificity, expression profiles, and binding locations of four histone deacetylases (HDACs), representing the three different phylogenetic classes in fission yeast (Schizosaccharomyces pombe). By directly comparing nucleosome density, histone acetylation patterns and HDAC binding in both intergenic and coding regions with gene expression profiles, we found that Sir2 (class III) and Hos2 (class I) have a role in preventing histone loss; Clr6 (class I) is the principal enzyme in promoter-localized repression. Hos2 has an unexpected role in promoting high expression of growth-related genes by deacetylating H4K16Ac in their open reading frames. Clr3 (class II) acts cooperatively with Sir2 throughout the genome, including the silent regions: rDNA, centromeres, mat2/3 and telomeres. The most significant acetylation sites are H3K14Ac for Clr3 and H3K9Ac for Sir2 at their genomic targets. Clr3 also affects subtelomeric regions which contain clustered stress- and meiosis-induced genes. Thus, this combined genomic approach has uncovered different roles for fission yeast HDACs at the silent regions in repression and activation of gene expression. PMID:16079916

Wirén, Marianna; Silverstein, Rebecca A; Sinha, Indranil; Walfridsson, Julian; Lee, Hang-Mao; Laurenson, Patricia; Pillus, Lorraine; Robyr, Daniel; Grunstein, Michael; Ekwall, Karl

2005-08-17

221

Genomewide analysis of nucleosome density histone acetylation and HDAC function in fission yeast  

PubMed Central

We have conducted a genomewide investigation into the enzymatic specificity, expression profiles, and binding locations of four histone deacetylases (HDACs), representing the three different phylogenetic classes in fission yeast (Schizosaccharomyces pombe). By directly comparing nucleosome density, histone acetylation patterns and HDAC binding in both intergenic and coding regions with gene expression profiles, we found that Sir2 (class III) and Hos2 (class I) have a role in preventing histone loss; Clr6 (class I) is the principal enzyme in promoter-localized repression. Hos2 has an unexpected role in promoting high expression of growth-related genes by deacetylating H4K16Ac in their open reading frames. Clr3 (class II) acts cooperatively with Sir2 throughout the genome, including the silent regions: rDNA, centromeres, mat2/3 and telomeres. The most significant acetylation sites are H3K14Ac for Clr3 and H3K9Ac for Sir2 at their genomic targets. Clr3 also affects subtelomeric regions which contain clustered stress- and meiosis-induced genes. Thus, this combined genomic approach has uncovered different roles for fission yeast HDACs at the silent regions in repression and activation of gene expression. PMID:16079916

Wirén, Marianna; Silverstein, Rebecca A; Sinha, Indranil; Walfridsson, Julian; Lee, Hang-mao; Laurenson, Patricia; Pillus, Lorraine; Robyr, Daniel; Grunstein, Michael; Ekwall, Karl

2005-01-01

222

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

223

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

224

Novel (64)Cu-Labeled CUDC-101 for in Vivo PET Imaging of Histone Deacetylases.  

PubMed

We report the design, synthesis, and biological evaluation of a (64)Cu-labeled histone deacetylase (HDAC) imaging probe, which was obtained by introduction of metal chelator through click reaction of HDAC inhibitor CUDC-101 and then radiolabeled with (64)Cu. The resulting (64)Cu-labeled compound 7 ([(64)Cu]7) was identified as a positron emission tomography (PET) imaging probe to noninvasively visualize HDAC expression in vivo. Cell based competitive assay established the specific binding of [(64)Cu]7 to HDACs. Biodistribution and small-animal microPET/CT studies further showed that [(64)Cu]7 had high tumor to background ratio in the MDA-MB-231 xenograft model, a triple-negative breast cancer with high expression of HDACs. To our knowledge, [(64)Cu]7 thus represents the first (64)Cu-labeled PET HDAC imaging probe, which exhibits nanomolar range binding affinity and capability to imaging HDAC expression in triple-negative breast cancer in vivo. PMID:24900760

Meng, Qingqing; Li, Feng; Jiang, Sheng; Li, Zheng

2013-09-12

225

Novel 64Cu-Labeled CUDC-101 for in Vivo PET Imaging of Histone Deacetylases  

PubMed Central

We report the design, synthesis, and biological evaluation of a 64Cu-labeled histone deacetylase (HDAC) imaging probe, which was obtained by introduction of metal chelator through click reaction of HDAC inhibitor CUDC-101 and then radiolabeled with 64Cu. The resulting 64Cu-labeled compound 7 ([64Cu]7) was identified as a positron emission tomography (PET) imaging probe to noninvasively visualize HDAC expression in vivo. Cell based competitive assay established the specific binding of [64Cu]7 to HDACs. Biodistribution and small-animal microPET/CT studies further showed that [64Cu]7 had high tumor to background ratio in the MDA-MB-231 xenograft model, a triple-negative breast cancer with high expression of HDACs. To our knowledge, [64Cu]7 thus represents the first 64Cu-labeled PET HDAC imaging probe, which exhibits nanomolar range binding affinity and capability to imaging HDAC expression in triple-negative breast cancer in vivo. PMID:24900760

2013-01-01

226

Radionuclide labeling and evaluation of candidate radioligands for PET imaging of histone deacetylase in the brain.  

PubMed

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-([(18)F]Fluoroacetamido)-1-hexanoicanilide ([(18)F]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 [(18)F]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

2013-12-15

227

Effects of the Histone Deacetylase Inhibitor Valproic Acid on Human Pericytes In Vitro  

PubMed Central

Microvascular pericytes are of key importance in neoformation of blood vessels, in stabilization of newly formed vessels as well as maintenance of angiostasis in resting tissues. Furthermore, pericytes are capable of differentiating into pro-fibrotic collagen type I producing fibroblasts. The present study investigates the effects of the histone deacetylase (HDAC) inhibitor valproic acid (VPA) on pericyte proliferation, cell viability, migration and differentiation. The results show that HDAC inhibition through exposure of pericytes to VPA in vitro causes the inhibition of pericyte proliferation and migration with no effect on cell viability. Pericyte exposure to the potent HDAC inhibitor Trichostatin A caused similar effects on pericyte proliferation, migration and cell viability. HDAC inhibition also inhibited pericyte differentiation into collagen type I producing fibroblasts. Given the importance of pericytes in blood vessel biology a qPCR array focusing on the expression of mRNAs coding for proteins that regulate angiogenesis was performed. The results showed that HDAC inhibition promoted transcription of genes involved in vessel stabilization/maturation in human microvascular pericytes. The present in vitro study demonstrates that VPA influences several aspects of microvascular pericyte biology and suggests an alternative mechanism by which HDAC inhibition affects blood vessels. The results raise the possibility that HDAC inhibition inhibits angiogenesis partly through promoting a pericyte phenotype associated with stabilization/maturation of blood vessels. PMID:21966390

Friman, Tomas; Dencker, Lennart; Sundberg, Christian; Scholz, Birger

2011-01-01

228

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

229

Redox Signaling, Alkylation (Carbonylation) of Conserved Cysteines Inactivates Class I Histone Deacetylases 1, 2, and 3 and Antagonizes Their Transcriptional Repressor Function*  

PubMed Central

Cells use redox signaling to adapt to oxidative stress. For instance, certain transcription factors exist in a latent state that may be disrupted by oxidative modifications that activate their transcription potential. We hypothesized that DNA-binding sites (response elements) for redox-sensitive transcription factors may also exist in a latent state, maintained by co-repressor complexes containing class I histone deacetylase (HDAC) enzymes, and that HDAC inactivation by oxidative stress may antagonize deacetylase activity and unmask electrophile-response elements, thus activating transcription. Electrophiles suitable to test this hypothesis include reactive carbonyl species, often derived from peroxidation of arachidonic acid. We report that ?,?-unsaturated carbonyl compounds, e.g. the cyclopentenone prostaglandin, 15-deoxy-?12,14-PGJ2 (15d-PGJ2), and 4-hydroxy-2-nonenal (4HNE), alkylate (carbonylate), a subset of class I HDACs including HDAC1, -2, and -3, but not HDAC8. Covalent modification at two conserved cysteine residues, corresponding to Cys261 and Cys273 in HDAC1, coincided with attenuation of histone deacetylase activity, changes in histone H3 and H4 acetylation patterns, derepression of a LEF1·?-catenin model system, and transcription of HDAC-repressed genes, e.g. heme oxygenase-1 (HO-1), Gadd45, and HSP70. Identification of particular class I HDACs as components of the redox/electrophile-responsive proteome offers a basis for understanding how cells stratify their responses to varying degrees of pathophysiological oxidative stress associated with inflammation, cancer, and metabolic syndrome. PMID:20385560

Doyle, Kelly; Fitzpatrick, F. A.

2010-01-01

230

The C. elegans histone deacetylase HDA-1 is required for cell migration and axon pathfinding.  

PubMed

Histone proteins play integral roles in chromatin structure and function. Histones are subject to several types of posttranslational modifications, including acetylation, which can produce transcriptional activation. The converse, histone deacetylation, is mediated by histone deacetylases (HDACs) and often is associated with transcriptional silencing. We identified a new mutation, cw2, in the Caenorhabditis elegans hda-1 gene, which encodes a histone deacetylase. Previous studies showed that a mutation in hda-1, e1795, or reduction of hda-1 RNA by RNAi causes defective vulval and gonadal development leading to sterility. The hda-1(cw2) mutation causes defective vulval development and reduced fertility, like hda-1(e1795), albeit with reduced severity. Unlike the previously reported hda-1 mutation, hda-1(cw2) mutants are viable as homozygotes, although many die as embryos or larvae, and are severely uncoordinated. Strikingly, in hda-1(cw2) mutants, axon pathfinding is defective; specific axons often appear to wander randomly or migrate in the wrong direction. In addition, the long range migrations of three neuron types and fasciculation of the ventral nerve cord are defective. Together, our studies define a new role for HDA-1 in nervous system development, and provide the first evidence for HDAC function in regulating neuronal axon guidance. PMID:16313898

Zinovyeva, Anna Y; Graham, Serena M; Cloud, Veronica J; Forrester, Wayne C

2006-01-01

231

Inhibition of histone deacetylase activity down-regulates urokinase plasminogen activator and matrix metalloproteinase-9 expression in gastric cancer.  

PubMed

Histone acetylation and deacetylaion play important roles in chromatin remodeling and gene expression. An imbalance of these reactions leads to aberrant behavior of the cells in the cell cycle, which in turn contributes to carcinogenesis. Histone deacetylase (HDAC) inhibitors have been shown to have anti-tumor effects in clinical trials. However, the exact mechanisms by which HDAC inhibitors exert anti-tumor effects and modulate gene expression are not completely understood, and remain a subject of intense investigation. In the current study, we determined whether HDACs regulate urokinase plasminogen activator (uPA), matrix metalloproteinase-9 (MMP-9), and tumor invasion. Using cDNA microarray analysis, we found that hepatocyte growth factor (HGF) induced HDAC5 expression in gastric cancer cell lines, NUGC-3 and MKN-28. TSA, a HDAC inhibitor, decreased HGF-induced HADC-5 expression and also repressed uPA and MMP-9 expression. TSA inhibited cell proliferation in both cell lines. In vitro Matrigel invasion assays showed that the HDAC inhibitor decreased cancer cell invasion. Furthermore, GO6976, a PKC inhibitor, significantly inhibited not only HGF-induced HDAC5 expression but also cell invasion. These results demonstrated that HDACs regulate HGF-induced uPA and MMP-9 expression through a PKC-dependent signal pathway in gastric cancer cells. Our data probably suggest that such activities serve as anti-tumor mechanisms of the HDAC inhibitor. PMID:20559690

Lee, Kyung Hee; Choi, Eun Young; Kim, Min Kyoung; Kim, Kyeong Ok; Jang, Byung Ik; Kim, Se Won; Kim, Sang Woon; Song, Sun Kyo; Kim, Jae-Ryong

2010-10-01

232

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

233

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

234

Inhibition of Histone Deacetylase by Butyrate Protects Rat Liver from Ischemic Reperfusion Injury  

PubMed Central

We showed previously that pretreatment of butyrate, which is an endogenous histone deacetylase (HDAC) inhibitor normally fermented from undigested fiber by intestinal microflora, seriously alleviated ischemia reperfusion (I/R)-induced liver injury by inhibiting the nuclear factor ?B (NF-?B) pathway. The goal of this study was to investigate the effect of butyrate administrated at the onset of ischemia for HDAC inhibition in hepatic I/R injury. Sprague Dawley rats were subjected to warm ischemia for 60 min followed by 6 and 24 h of reperfusion. Butyrate was administrated at the onset of ischemia. Liver injury was evaluated by serum levels of aminotransferase, inflammatory factors, and histopathology. The levels of acetylated histone H3 and expression of heat shock protein (Hsp) 70 were measured by Western blot. After reperfusion, the levels of acetylated histone H3 significantly decreased. Butyrate treatment markedly prevented the reduction of acetylated histone H3 and upregulated the expression of Hsp70, thereby reducing liver injury. Our study demonstrated that I/R resulted in marked reduction of histone acetylation; butyrate exerted a great hepatoprotective effect through HDAC inhibition and Hsp70 induction. PMID:25405737

Sun, Jie; Wu, Qiujv; Sun, Huiling; Qiao, Yingli

2014-01-01

235

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

236

Differential regulation of the Sir2 histone deacetylase gene family by inhibitors of class I and II histone deacetylases  

Microsoft Academic Search

The Sir2 histone deacetylase gene family consists of seven mammalian sirtuins (SIRTs) which are NAD-dependent histone\\/protein deacetylases. Sir2 proteins regulate, for instance, genome stability by chromatin silencing in yeast. In mammals, their function is still largely unknown. Due to the NAD + dependency, Sir2 might be the link between metabolic activity and histone\\/protein acetylation. Regulation of gene expression also seems

S. Kyrylenko; O. Kyrylenko; T. Suuronen; A. Salminen

2003-01-01

237

Histone deacetylases and epigenetic therapies of hematological malignancies  

Microsoft Academic Search

Histone deacetylase inhibitors (HDACi) represent a novel class of targeted drugs which alter the acetylation status of several cellular proteins. These agents, modulating both chromatin structure through histone acetylation, and the activity of several non-histone substrates, are at the same time able to determine changes in gene transcription and to induce a plethora of biological effects ranging from cell death

Ciro Mercurio; Saverio Minucci; Pier Giuseppe Pelicci

2010-01-01

238

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

239

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

PubMed

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; Reddy, Pavan

2015-01-29

240

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

241

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

242

HISTONE DEACETYLASE 9 represses seedling traits in Arabidopsis thaliana dry seeds.  

PubMed

Plant life is characterized by major phase changes. We studied the role of histone deacetylase (HDAC) activity in the transition from seed to seedling in Arabidopsis. Pharmacological inhibition of HDAC stimulated germination of freshly harvested seeds. Subsequent analysis revealed that histone deacetylase 9 (hda9) mutant alleles displayed reduced seed dormancy and faster germination than wild-type plants. Transcriptome meta-analysis comparisons between the hda9 dry seed transcriptome and published datasets demonstrated that transcripts of genes that are induced during imbibition in wild-type prematurely accumulated in hda9-1 dry seeds. This included several genes associated with photosynthesis and photoautotrophic growth such as RuBisCO and RuBisCO activase (RCA). Chromatin immunoprecipitation experiments demonstrated enhanced histone acetylation levels at their loci in young hda9-1 seedlings. Our observations suggest that HDA9 negatively influences germination and is involved in the suppression of seedling traits in dry seeds, probably by transcriptional repression via histone deacetylation. Accordingly, HDA9 transcript is abundant in dry seeds and becomes reduced during imbibition in wild-type seeds. The proposed function of HDA9 is opposite to that of its homologous genes HDA6 and HDA19, which have been reported to repress embryonic properties in germinated seedlings. PMID:25146719

van Zanten, Martijn; Zöll, Christian; Wang, Zhi; Philipp, Christina; Carles, Annaick; Li, Yong; Kornet, Noortje G; Liu, Yongxiu; Soppe, Wim J J

2014-11-01

243

Drosophila histone deacetylase 6 protects dopaminergic neurons against {alpha}-synuclein toxicity by promoting inclusion formation.  

PubMed

Parkinson's disease (PD) is associated with progressive degeneration of dopaminergic (DA) neurons. We report for the first time that the Drosophila histone deacetylase 6 (dHDAC6) plays a critical role in the protection of DA neurons and the formation of alpha-synuclein inclusions by using a Drosophila PD model constructed by ectopic expression of human alpha-synuclein. Depletion of dHDAC6 significantly enhances the effects caused by ectopic expression of alpha-synuclein, namely, loss of DA neurons, retinal degeneration, and locomotor dysfunction. Expression of alpha-synuclein in the DA neurons leads to fewer inclusions in the brains of dHDAC6 mutant flies than in wild-type flies. Conversely, overexpression of dHDAC6 is able to suppress the alpha-synuclein-induced DA neuron loss and retinal degeneration and promote inclusion formation. Furthermore, mutation of dHDAC6 reinforces the accumulation of oligomers that are suggested to be a toxic form of alpha-synuclein. We propose that alpha-synuclein inclusion formation in the presence of dHDAC6 protects DA neurons from being damaged by oligomers, which may uncover a common mechanism for synucleinopathies. PMID:20444973

Du, Guiping; Liu, Xiang; Chen, Xinping; Song, Mei; Yan, Yan; Jiao, Renjie; Wang, Chih-Chen

2010-07-01

244

Blocking TH17-polarizing cytokines by histone deacetylase inhibitors in vitro and in vivo  

PubMed Central

Histone deacetylase (HDAC) inhibitors are small molecules inducing cell-cycle arrest, differentiation, and apoptosis, currently undergoing clinical trials as anticancer drugs. In addition, emerging evidence suggests HDAC inhibitors may have anti-inflammatory and immunomodulatory properties as well, although the molecular mechanisms remain poorly defined. Given the central role of dendritic cells (DC) in the induction and maintenance of the inflammatory and immune response, we investigated the effects of HDAC inhibitors on the maturation and activation of human monocyte-derived DC in the presence of LPS and IFN-?. Our results show that the production of TH1- and TH17-inducing cytokines, namely IL-12 and IL-23, was inhibited by trichostatin A (72% and 52%, respectively) and suberoylanilide hydroxamic acid (86% and 83%). Strikingly, HDAC inhibitors were effective if added simultaneously as well as after the proinflammatory challenge, and their effect was not associated to a reduction of expression or function of LPS/IFN-? receptors. These findings were confirmed in two different murine models. In addition, HDAC inhibitors selectively blocked the production of TH1-attracting chemokines CXCL9, CXCL10, and CXCL11. The reduction of TH1- and TH17-inducing cytokines as well as TH1-attracting chemokines may represent relevant mechanisms through which HDAC inhibitors at nonproapoptotic doses exert their immunomodulatory properties. PMID:18780875

Bosisio, Daniela; Vulcano, Marisa; Del Prete, Annalisa; Sironi, Marina; Salvi, Valentina; Salogni, Laura; Riboldi, Elena; Leoni, Flavio; Dinarello, Charles A.; Girolomoni, Giampiero; Sozzani, Silvano

2008-01-01

245

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

PubMed Central

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

2014-01-01

246

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

247

Histone deacetylase inhibitor for NUT midline carcinoma.  

PubMed

NUT Midline carcinoma (NMC) is a rare and invariably fatal poorly differentiated carcinoma characterized by chromosomal rearrangement involving the nuclear protein of the testis (NUT) gene. Current approaches do not provide durable response. We report a case of widely metastatic NMC in a 17-year-old female who, following an initial response to combination chemotherapy developed rapid disease progression. Treatment with vorinostat, a histone deacetylase inhibitor (HDACi) resulted in an objective response, yet she died in less than one year from initial diagnosis. This report shows a potentially promising activity of HDACi in the treatment of NMC that needs further exploration. Pediatr Blood Cancer 2015;62:715-717. © 2015 Wiley Periodicals, Inc. PMID:25557064

Maher, Ossama M; Christensen, Anthony M; Yedururi, Sireesha; Bell, Diana; Tarek, Nidale

2015-04-01

248

Histone deacetylase inhibitors: emerging mechanisms of resistance  

PubMed Central

The histone deacetylase inhibitors (HDIs) have shown promise in the treatment of a number of hematologic malignancies, leading to the approval of vorinostat and romidepsin for the treatment of cutaneous T-cell lymphoma and romidepsin for the treatment of peripheral T-cell lymphoma by the U. S. Food and Drug Administration. Despite these promising results, clinical trials with the HDIs in solid tumors have not met with success. Examining mechanisms of resistance to HDIs may lead to strategies that increase their therapeutic potential in solid tumors. However, relatively few examples of drug-selected cell lines exist, and mechanisms of resistance have not been studied in depth. Very few clinical translational studies have evaluated resistance mechanisms. In the current review, we summarize many of the purported mechanisms of action of the HDIs in clinical trials and examine some of the emerging resistance mechanisms. PMID:21899343

Robey, Robert W.; Chakraborty, Arup R.; Basseville, Agnes; Luchenko, Victoria; Bahr, Julian; Zhan, Zhirong; Bates, Susan E.

2011-01-01

249

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

PubMed Central

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

2014-01-01

250

HDAC6 deacetylation of tubulin modulates dynamics of cellular adhesions  

Microsoft Academic Search

Genetic or pharmacological alteration of the activity of the histone deacetylase 6 (HDAC6) induces a parallel alteration in cell migration. Using tubacin to block deacetylation of -tubulin, and not other HDAC6 substrates, yielded a motility reduction equivalent to agents that block all NAD- independent HDACs. Accordingly, we investigated how the failure to deacetylate tubulin contributes to decreased motility in HDAC6-inhibited

Andy Dong-Anh Tran; Timothy P. Marmo; Ambar A. Salam; Sally Che; Erik Finkelstein; Rafi Kabarriti; Harry S. Xenias; Ralph Mazitschek; Charlotte Hubbert; Yoshiharu Kawaguchi; Michael P. Sheetz; Tso-Pang Yao; J. Chloë Bulinski

2007-01-01

251

Histone deacetylase inhibitors and genomic instability. Grgory Eot-Houllier  

E-print Network

to the cytotoxic effects of these drugs. Indeed, HDACIs sensitize DNA to exogenous genotoxic damage and induce.06.005 #12;Abstract: Histone deacetylase inhibitors (HDACIs) are a promising new class of anticancer drugs

Paris-Sud XI, Université de

252

Histone deacetylase inhibitor-polymer conjugate nanoparticles for acid-responsive drug delivery.  

PubMed

We report the synthesis of acid-responsive polymeric nanoparticles (NPs) consisting of a polymer-histone deacetylase inhibitor conjugate. An innovative aspect of this drug delivery particle lies in the NP conjugation of a histone deacetylase (HDAC) inhibitor, CI-994 (Tacedinaline), introduced with a clickable acid-responsive prodrug during monomer synthesis, prior to polymerization. Another novelty lies in the selected norbornene (NB)-polyethylene oxide (PEO) macromonomer allowing standardization of the polymerization process by Ring-Opening Metathesis Polymerization (ROMP) and functionalization through azide-alkyne click chemistry. Herein we demonstrate that the synthesized polymer gave 300 nm core-shell spherical nanoparticles with low dispersity (0.04), high water dispersability thanks to the PEO shell and well controlled HDAC inhibitor prodrug loading. Bioluminescence Resonance Energy Transfer (BRET) assay in living cells and viability experiments demonstrated efficient cellular internalization without additional chemistry, drug release inside cells with restoration of the HDAC inhibition and induction of apoptosis. Such NPs should minimize drug release in vivo during blood circulation and trigger intracellular delivery after endocytosis, holding promises for improved efficacy of this class of epigenetic inhibitors. This standardized synthesis paves the way for multifunctional nanoparticles synthesis. PMID:25827403

Denis, Iza; El Bahhaj, Fatima; Collette, Floraine; Delatouche, Régis; Gueugnon, Fabien; Pouliquen, Daniel; Pichavant, Loic; Héroguez, Valérie; Grégoire, Marc; Bertrand, Philippe; Blanquart, Christophe

2015-05-01

253

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

254

DNA methyltransferase Dnmt1 associates with histone deacetylase activity  

Microsoft Academic Search

The DNA methyltransferase Dnmt1 is responsible for cytosine methylation in mammals and has a role in gene silencing. DNA methylation represses genes partly by recruitment of the methyl-CpG-binding protein MeCP2, which in turn recruits a histone deacetylase activity. Here we show that Dnmt1 is itself associated with histone deacetylase activity in vivo. Consistent with this association, we find that one

François Fuks; Wendy A. Burgers; Alexander Brehm; Luke Hughes-Davies; Tony Kouzarides

2000-01-01

255

Trichostatin A induces 5-lipoxygenase promoter activity and mRNA expression via inhibition of histone deacetylase 2 and 3  

PubMed Central

Abstract The 5-lipoxygenase (5-LO) is the key enzyme in the formation of leukotrienes. We have previously shown that the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) activates 5-LO transcription via recruitment of Sp1, Sp3 and RNA polymerase II to the proximal promoter. To identify the HDACs involved in the regulation of 5-LO promoter activity isoform-specific HDAC inhibitors were applied. 5-LO promoter activity and mRNA expression were up-regulated by the class I HDAC inhibitors apicidin and MS-275 but not by class II inhibitors. Knockdown of HDAC 1, 2 and 3 revealed that HDAC2 and HDAC3 but not HDAC1 is involved in the up-regulation of 5-LO mRNA expression. To analyse the chromatin modifications at the 5-LO promoter associated with HDAC inhibition, the time course of 5-LO mRNA induction by trichostatin A was investigated and the concomitant changes in histone modifications at the 5-LO promoter in HL-60, U937 and Mono Mac6 cells were determined. Chromatin immunoprecipitation analysis revealed that trichostatin A increases acetylation of histones H3 and H4 at the 5-LO core promoter in HL-60 and U937 cells whereas no significant changes were observed in Mono Mac6 cells. The appearance of H3 and H4 acetylation preceded the 5-LO mRNA induction whereas in all three cell lines, induction of 5-LO mRNA expression correlated with histone H3 lysine 4 trimethylation (H3K4me3), a marker for transcriptional activity of gene promoters. PMID:21883892

Pufahl, Laura; Katryniok, Careen; Schnur, Nicole; Sorg, Bernd L; Metzner, Julia; Grez, Manuel; Steinhilber, Dieter

2012-01-01

256

Regulation of Neuronal Gene Expression and Survival by Basal NMDA Receptor Activity: A Role for Histone Deacetylase 4  

PubMed Central

Neuronal gene expression is modulated by activity via calcium-permeable receptors such as NMDA receptors (NMDARs). While gene expression changes downstream of evoked NMDAR activity have been well studied, much less is known about gene expression changes that occur under conditions of basal neuronal activity. In mouse dissociated hippocampal neuronal cultures, we found that a broad NMDAR antagonist, AP5, induced robust gene expression changes under basal activity, but subtype-specific antagonists did not. While some of the gene expression changes are also known to be downstream of stimulated NMDAR activity, others appear specific to basal NMDAR activity. The genes altered by AP5 treatment of basal cultures were enriched for pathways related to class IIa histone deacetylases (HDACs), apoptosis, and synapse-related signaling. Specifically, AP5 altered the expression of all three class IIa HDACs that are highly expressed in the brain, HDAC4, HDAC5, and HDAC9, and also induced nuclear accumulation of HDAC4. HDAC4 knockdown abolished a subset of the gene expression changes induced by AP5, and led to neuronal death under long-term tetrodotoxin or AP5 treatment in rat hippocampal organotypic slice cultures. These data suggest that basal, but not evoked, NMDAR activity regulates gene expression in part through HDAC4, and, that HDAC4 has neuroprotective functions under conditions of low NMDAR activity. PMID:25392500

Chen, Yelin; Wang, Yuanyuan; Modrusan, Zora

2014-01-01

257

Histone deacetylase 6 and heat shock protein 90 control the functions of Foxp3(+) T-regulatory cells.  

PubMed

Foxp3(+) T-regulatory cells (Tregs) are key to immune homeostasis such that their diminished numbers or function can cause autoimmunity and allograft rejection. Foxp3(+) Tregs express multiple histone/protein deacetylases (HDACs) that regulate chromatin remodeling, gene expression, and protein function. Pan-HDAC inhibitors developed for oncologic applications enhance Treg production and Treg suppression function but have limited nononcologic utility given their broad actions and various side effects. We show, using HDAC6-deficient mice and wild-type (WT) mice treated with HDAC6-specific inhibitors, that HDAC6 inhibition promotes Treg suppressive activity in models of inflammation and autoimmunity, including multiple forms of experimental colitis and fully major histocompatibility complex (MHC)-incompatible cardiac allograft rejection. Many of the beneficial effects of HDAC6 targeting are also achieved by inhibition of the HDAC6-regulated protein heat shock protein 90 (HSP90). Hence, selective targeting of a single HDAC isoform, HDAC6, or its downstream target, HSP90, can promote Treg-dependent suppression of autoimmunity and transplant rejection. PMID:21444725

de Zoeten, Edwin F; Wang, Liqing; Butler, Kyle; Beier, Ulf H; Akimova, Tatiana; Sai, Hong; Bradner, James E; Mazitschek, Ralph; Kozikowski, Alan P; Matthias, Patrick; Hancock, Wayne W

2011-05-01

258

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

259

Synergistic Activation of Functional Estrogen Receptor (ER)- by DNA Methyltransferase and Histone Deacetylase Inhibition in Human ER--negative Breast Cancer Cells1  

Microsoft Academic Search

Formation of transcriptional repression complexes such as DNA meth- yltransferase (DNMT) 1\\/histone deacetylase (HDAC) or methyl-CpG binding protein\\/HDAC is emerging as an important mechanism in silenc- ing a variety of methylated tissue-specific and imprinted genes. Our previous studies showed that treatment of estrogen receptor (ER)-- negative human breast cancer cells with the DNMT inhibitor 5-aza-2- deoxycytidine (5-aza-dC) led to ER

Dawn L. Phillips; Anne T. Ferguson; William G. Nelson; James G. Herman; Nancy E. Davidson

2000-01-01

260

Histone Deacetylase Inhibitors Decrease DNA Methyltransferase3B Messenger RNA Stability and Down-regulate De novo DNA Methyltransferase Activity in Human Endometrial Cells  

Microsoft Academic Search

It is well known that the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) acts synergistically with the DNA methyltransferase (DNMT) inhibitor 5-aza-2V-deoxycytidine (ADC) to reactivate DNA methylation-silenced genes. More- over, in several studies, TSA was capable of inducing DNA demethylation even in the absence of ADC. Here we describe a mechanism by which HDAC inhibitors affect DNA methylation through their

Yuning Xiong; Sean C. Dowdy; Karl C. Podratz; Fan Jin; John R. Attewell; Norman L. Eberhardt; Shi-Wen Jiang

2005-01-01

261

Histone deacetylase 3 promotes pancreatic cancer cell proliferation, invasion and increases drug-resistance through histone modification of P27, P53 and Bax.  

PubMed

Pancreatic cancer is one of the most aggressive solid malignancies with a dismal survival rate. Recent studies have shown that high expression levels of histone deacetylase 3 (HDAC3) correlate with malignant phenotype. However, the expression patterns and biological role of HDAC3 in pancreatic cancer remain unclear. In this study, our data showed that a higher level of HDAC3 protein expression was found in pancreatic cancer as compared to paired paracancerous tissues. Consistently, higher expression level of HDAC3 was found in all of the eight pancreatic cancer cell lines relative to human pancreatic ductal epithelial cells (HPDE). In addition, further function analysis revealed that HDAC3 can function as oncogenic protein, which could promote pancreatic cancer cell proliferation, migration and invasion, and may increase drug resistance. Moreover, the functional involvement of HDAC3 was partially correlated with post-induction repression of P53, P27 and Bax gene transcription, acting via H3K9 deacetylation. Taken together, our data suggest that HDAC3 participates in the pathogenesis and progression of pancreatic cancer through histone modification, which might be a pivotal epigenetic target against this devastating disease. PMID:25070540

Jiao, Feng; Hu, Hai; Yuan, Cuncun; Jin, Ziliang; Guo, Zhen; Wang, Liwei; Wang, Lei

2014-10-01

262

Trichostatin A, a histone deacetylase inhibitor, suppresses proliferation and promotes apoptosis of esophageal squamous cell lines.  

PubMed

Histone deacetylase (HDAC)?mediated epigenetic modification plays crucial roles in numerous biological processes, including cell cycle regulation, cell proliferation and apoptosis. HDAC inhibitors demonstrate antitumor effects in various cancers, including glioblastoma and breast cancer. HDAC inhibitors are therefore promising antitumor drugs for these tumors. The tumorigenesis and development of esophageal squamous cell carcinoma (ESCC) involve genetic and epigenetic mechanisms. However, the effects of the HDAC inhibitor on ESCC are not fully investigated. In the present study, ESCC cells were treated with trichostatin A (TSA) and its antitumor effects and related mechanisms were investigated. The results indicated that TSA suppressed the proliferation of ESCCs and caused G1 phase arrest by inducing the expression of p21 and p27. TSA also induced cell apoptosis by enhancing the expression of pro?apoptotic protein Bax and decreasing the expression of anti?apoptotic protein Bcl?2. Furthermore, TSA inhibited the expression of phosphatidylinositol?3?kinase (PI3K) and reduced the phosphorylation of Akt and extracellular signal?regulated kinase (ERK)1/2 in EC9706 and EC1 cell lines. High levels of acetylated histone H4 were detected in TSA?treated ESCC cell lines. Overall, these results indicate that TSA suppresses ESCC cell growth by inhibiting the activation of the PI3K/Akt and ERK1/2 pathways. TSA also promotes cell apoptosis through epigenetic regulation of the expression of apoptosis?related protein. PMID:25634603

Ma, Junfen; Guo, Xiaobing; Zhang, Shijie; Liu, Hongchun; Lu, Jing; Dong, Ziming; Liu, Kangdong; Ming, Liang

2015-06-01

263

Inhibition of histone deacetylases enhances the function of serotoninergic neurons in organotypic raphe slice cultures.  

PubMed

Inhibition of histone deacetylases (HDACs) is a promising approach for the treatment of mood disorders. However, the effects of HDAC inhibition on the serotonin (5-HT) system, a common target for psychiatric disorders, are poorly understood. Here, we show that a broad-spectrum HDAC inhibitor, trichostatin A (TSA), enhances the function of 5-HT neurons in organotypic raphe slice cultures. Sustained treatment with TSA (1?M) for 2 or 4 days significantly increased the 5-HT tissue content and tryptophan hydroxylase 2 (TPH2) expression, which were accompanied by hyper-acetylation of histone H3 in the promoter region of the TPH2 gene. TSA treatment for 4 days increased the extracellular 5-HT level, which was significantly suppressed in the presence of the selective AMPA receptor (AMPAR) antagonist NBQX. Moreover, the expression of both the AMPAR subunit GluA2 and Ca(2+)/calmodulin-dependent kinase II ? (CaMKII?) mRNAs were significantly increased by TSA treatment. Co-treatment with the CaMKII inhibitors KN-62 and KN-93 prevented the TSA-induced increase in 5-HT release, but had no effect on the increases in 5-HT tissue content. These results suggest that inhibition of HDACs increases 5-HT synthesis and release by epigenetic mechanisms, and that 5-HT release is mediated by the enhancement of AMPAR-mediated excitatory inputs and CaMKII signaling. PMID:25796177

Asaoka, Nozomi; Nagayasu, Kazuki; Nishitani, Naoya; Yamashiro, Mayumi; Shirakawa, Hisashi; Nakagawa, Takayuki; Kaneko, Shuji

2015-04-23

264

A novel histone deacetylase complex in the control of transcription and genome stability.  

PubMed

The acetylation state of histones, controlled by histone acetyltransferases (HATs) and deacetylases (HDACs), profoundly affects DNA transcription and repair by modulating chromatin accessibility to the cellular machinery. The Schizosaccharomyces pombe HDAC Clr6 (human HDAC1) binds to different sets of proteins that define functionally distinct complexes: I, I', and II. Here, we determine the composition, architecture, and functions of a new Clr6 HDAC complex, I'', delineated by the novel proteins Nts1, Mug165, and Png3. Deletion of nts1 causes increased sensitivity to genotoxins and deregulated expression of Tf2 elements, long noncoding RNA, and subtelomeric and stress-related genes. Similar, but more pervasive, phenotypes are observed upon Clr6 inactivation, supporting the designation of complex I'' as a mediator of a key subset of Clr6 functions. We also reveal that with the exception of Tf2 elements, the genome-wide loading sites and loci regulated by Clr6 I? do not correlate. Instead, Nts1 loads at genes that are expressed in midmeiosis, following oxidative stress, or are periodically expressed. Collective data suggest that Clr6 I'' has (i) indirect effects on gene expression, conceivably by mediating higher-order chromatin organization of subtelomeres and Tf2 elements, and (ii) direct effects on the transcription of specific genes in response to certain cellular or environmental stimuli. PMID:25002536

Zilio, Nicola; Codlin, Sandra; Vashisht, Ajay A; Bitton, Danny A; Head, Steven R; Wohlschlegel, James A; Bähler, Jürg; Boddy, Michael N

2014-09-15

265

A Novel Histone Deacetylase Complex in the Control of Transcription and Genome Stability  

PubMed Central

The acetylation state of histones, controlled by histone acetyltransferases (HATs) and deacetylases (HDACs), profoundly affects DNA transcription and repair by modulating chromatin accessibility to the cellular machinery. The Schizosaccharomyces pombe HDAC Clr6 (human HDAC1) binds to different sets of proteins that define functionally distinct complexes: I, I?, and II. Here, we determine the composition, architecture, and functions of a new Clr6 HDAC complex, I??, delineated by the novel proteins Nts1, Mug165, and Png3. Deletion of nts1 causes increased sensitivity to genotoxins and deregulated expression of Tf2 elements, long noncoding RNA, and subtelomeric and stress-related genes. Similar, but more pervasive, phenotypes are observed upon Clr6 inactivation, supporting the designation of complex I?? as a mediator of a key subset of Clr6 functions. We also reveal that with the exception of Tf2 elements, the genome-wide loading sites and loci regulated by Clr6 I? do not correlate. Instead, Nts1 loads at genes that are expressed in midmeiosis, following oxidative stress, or are periodically expressed. Collective data suggest that Clr6 I?? has (i) indirect effects on gene expression, conceivably by mediating higher-order chromatin organization of subtelomeres and Tf2 elements, and (ii) direct effects on the transcription of specific genes in response to certain cellular or environmental stimuli. PMID:25002536

Zilio, Nicola; Codlin, Sandra; Vashisht, Ajay A.; Bitton, Danny A.; Head, Steven R.; Wohlschlegel, James A.; Bähler, Jürg

2014-01-01

266

Inhibition of Plasmodium falciparum proliferation in vitro by double-stranded RNA directed against malaria histone deacetylase  

SciTech Connect

Acetylation and deacetylation of histones play important roles in transcription regulation, cell cycle progression and development events. The steady state status of histone acetylation is controlled by a dynamic equilibrium between competing histone acetylase and deacetylase (HDAC). We have used long PfHDAC-1 double-stranded (ds)RNA to interfere with its cognate mRNA expression and determined the effect on malaria parasite growth and development. Chloroquine- and pyrimethamine-resistant Plasmodium falciparum K1 strain was exposed to 1-25 {mu}g of dsRNA/ml of culture for 48 h and growth was determined by [{sup 3}H]-hypoxanthine incorporation and microscopic examination. Parasite culture treated with 10 {mu}g/ml pfHDAC-1 dsRNA exhibited 47% growth inhibition when compared with either untreated control or culture treated with an unrelated dsRNA. PfHDAC-1 dsRNA specifically blocked maturation of trophozoite to schizont stages and decreased PfHDAC-1 transcript 44% in treated trophozoites. These results indicate the potential of HDAC-1 as a target for development of novel antimalarials.

Sriwilaijaroen, N. [Faculty of Medicine, Thammasat University (Rangsit Campus), Pathumthani 12120 (Thailand); Boonma, S. [Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400 (Thailand); Attasart, P. [Institute of Molecular Biology and Genetics, Mahidol University, Salaya, Nakornpathom 73170 (Thailand); Pothikasikorn, J. [Department of Microbiology, Faculty of Science, Mahidol University, Bangkok 10400 (Thailand); Panyim, S. [Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400 (Thailand); Institute of Molecular Biology and Genetics, Mahidol University, Salaya, Nakornpathom 73170 (Thailand); Noonpakdee, W. [Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400 (Thailand)], E-mail: scwnp@mahidol.ac.th

2009-04-03

267

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

268

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

269

Histone Deacetylase Complex1 Expression Level Titrates Plant Growth and Abscisic Acid Sensitivity in Arabidopsis[C][W][OPEN  

PubMed Central

Histone deacetylation regulates gene expression during plant stress responses and is therefore an interesting target for epigenetic manipulation of stress sensitivity in plants. Unfortunately, overexpression of the core enzymes (histone deacetylases [HDACs]) has either been ineffective or has caused pleiotropic morphological abnormalities. In yeast and mammals, HDACs operate within multiprotein complexes. Searching for putative components of plant HDAC complexes, we identified a gene with partial homology to a functionally uncharacterized member of the yeast complex, which we called Histone Deacetylation Complex1 (HDC1). HDC1 is encoded by a single-copy gene in the genomes of model plants and crops and therefore presents an attractive target for biotechnology. Here, we present a functional characterization of HDC1 in Arabidopsis thaliana. We show that HDC1 is a ubiquitously expressed nuclear protein that interacts with at least two deacetylases (HDA6 and HDA19), promotes histone deacetylation, and attenuates derepression of genes under water stress. The fast-growing HDC1-overexpressing plants outperformed wild-type plants not only on well-watered soil but also when water supply was reduced. Our findings identify HDC1 as a rate-limiting component of the histone deacetylation machinery and as an attractive tool for increasing germination rate and biomass production of plants. PMID:24058159

Perrella, Giorgio; Lopez-Vernaza, Manuel A.; Carr, Craig; Sani, Emanuela; Gosselé, Veronique; Verduyn, Christoph; Kellermeier, Fabian; Hannah, Matthew A.; Amtmann, Anna

2013-01-01

270

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

271

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

272

Evaluation of functional groups on amino acids in cyclic tetrapeptides in histone deacetylase inhibition.  

PubMed

The naturally occurring cyclic tetrapeptide, chlamydocin, originally isolated from fungus Diheterospora chlamydosphoria, consists of ?-aminoisobutyric acid, L-phenylalanine, D-proline and an unusual amino acid (S)-2-amino-8-((S)-oxiran-2-yl)-8-oxooctanoic acid (Aoe) and inhibits the histone deacetylases (HDACs), a class of regulatory enzymes. The epoxyketone moiety of Aoe is the key functional group for inhibition. The cyclic tetrapeptide scaffold is supposed to play important role for effective binding to the surface of enzymes. In place of the epoxyketone group, hydroxamic acid and sulfhydryl group have been applied to design inhibitor ligands to zinc atom in catalytic site of HDACs. In the research for more potent HDAC inhibitors, we replaced the epoxyketone moiety of Aoe with different functional groups and synthesized a series of chlamydocin analogs as HDAC inhibitors. Among the functional groups, methoxymethylketone moiety showed as potent inhibition as the hydroxamic acid. On the contrary, we confirmed that borate, trifruoromethylketone, and 2-aminoanilide are almost inactive in HDAC inhibition. PMID:21638021

Islam, Md Shahidul; Bhuiyan, Mohammed P I; Islam, Md Nurul; Nsiama, Tienabe Kipassa; Oishi, Naoto; Kato, Tamaki; Nishino, Norikazu; Ito, Akihiro; Yoshida, Minoru

2012-06-01

273

Cell cycle checkpoint signaling involved in histone deacetylase inhibition and radiation-induced cell death.  

PubMed

In breast cancer, radiation has a central role in the treatment of brain metastasis, although tumor sensitivity might be limited. The tumor cell defense response to ionizing radiation involves activation of cell cycle checkpoint signaling. Histone deacetylase (HDAC) inhibitors, agents that cause hyperacetylation of histone proteins and thereby aberrations in the chromatin structure, may also override the DNA damage defense response and facilitate the radiation-induced mitotic cell death. In experimental metastasis models, the human breast carcinoma cell line MA-11 invariably disseminates to the central nervous system. We compared profiles of in vitro MA-11 cell cycle response to ionizing radiation and HDAC inhibition. After radiation exposure, the G2-M phase accumulation and the preceding repression of the G2 phase regulatory factors Polo-like kinase-1 and cyclin B1 required intact G2 checkpoint signaling through the checkpoint kinase CHK1, whereas the similar phenotypic changes observed with HDAC inhibition did not. MA-11 cells did not show radiation-induced expression of the G1 cell cycle inhibitor p21, indicative of a defective G1 checkpoint and consistent with a point mutation detected in the tumor suppressor TP53 gene. Increase in the p21 level, however, was observed with HDAC inhibition. Following pretreatment with the HDAC inhibitor, the efficiency of clonogenic regrowth after irradiation was reduced, which is in accordance with the concept of increased probability of mitotic cell death when the chromatin structure is disrupted. Among molecular cell cycle-targeted drugs currently in the pipeline for testing in early-phase clinical trials, HDAC inhibitors may have therapeutic potential as radiosensitizers. PMID:16093439

Nome, Ragnhild V; Bratland, Ase; Harman, Gunhild; Fodstad, Oystein; Andersson, Yvonne; Ree, Anne Hansen

2005-08-01

274

The histone deacetylase inhibitor SAHA acts in synergism with fenretinide and doxorubicin to control growth of rhabdoid tumor cells  

PubMed Central

Background Rhabdoid tumors are highly aggressive malignancies affecting infants and very young children. In many instances these tumors are resistant to conventional type chemotherapy necessitating alternative approaches. Methods Proliferation assays (MTT), apoptosis (propidium iodide/annexin V) and cell cycle analysis (DAPI), RNA expression microarrays and western blots were used to identify synergism of the HDAC (histone deacetylase) inhibitor SAHA with fenretinide, tamoxifen and doxorubicin in rhabdoidtumor cell lines. Results HDAC1 and HDAC2 are overexpressed in primary rhabdoid tumors and rhabdoid tumor cell lines. Targeting HDACs in rhabdoid tumors induces cell cycle arrest and apoptosis. On the other hand HDAC inhibition induces deregulated gene programs (MYCC-, RB program and the stem cell program) in rhabdoid tumors. These programs are in general associated with cell cycle progression. Targeting these activated pro-proliferative genes by combined approaches of HDAC-inhibitors plus fenretinide, which inhibits cyclinD1, exhibit strong synergistic effects on induction of apoptosis. Furthermore, HDAC inhibition sensitizes rhabdoid tumor cell lines to cell death induced by chemotherapy. Conclusion Our data demonstrate that HDAC inhibitor treatment in combination with fenretinide or conventional chemotherapy is a promising tool for the treatment of chemoresistant rhabdoid tumors. PMID:23764045

2013-01-01

275

MEF2 Is a Converging Hub for Histone Deacetylase 4 and Phosphatidylinositol 3-Kinase/Akt-Induced Transformation  

PubMed Central

The MEF2-class IIa histone deacetylase (HDAC) axis operates in several differentiation pathways and in numerous adaptive responses. We show here that nuclear active HDAC4 and HDAC7 display transforming capability. HDAC4 oncogenic potential depends on the repression of a limited set of genes, most of which are MEF2 targets. Genes verified as targets of the MEF2-HDAC axis are also under the influence of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway that affects MEF2 protein stability. A signature of MEF2 target genes identified by this study is recurrently repressed in soft tissue sarcomas. Correlation studies depicted two distinct groups of soft tissue sarcomas: one in which MEF2 repression correlates with PTEN downregulation and a second group in which MEF2 repression correlates with HDAC4 levels. Finally, simultaneous pharmacological inhibition of the PI3K/Akt pathway and of MEF2-HDAC interaction shows additive effects on the transcription of MEF2 target genes and on sarcoma cells proliferation. Overall, our work pinpoints an important role of the MEF2-HDAC class IIa axis in tumorigenesis. PMID:24043307

Di Giorgio, Eros; Clocchiatti, Andrea; Piccinin, Sara; Sgorbissa, Andrea; Viviani, Giulia; Peruzzo, Paolo; Romeo, Salvatore; Rossi, Sabrina; Dei Tos, Angelo Paolo; Maestro, Roberta

2013-01-01

276

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

277

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

278

Image-guided synthesis reveals potent blood-brain barrier permeable histone deacetylase inhibitors.  

PubMed

Recent studies have revealed that several histone deacetylase (HDAC) inhibitors, which are used to study/treat brain diseases, show low blood-brain barrier (BBB) penetration. In addition to low HDAC potency and selectivity observed, poor brain penetrance may account for the high doses needed to achieve therapeutic efficacy. Here we report the development and evaluation of highly potent and blood-brain barrier permeable HDAC inhibitors for CNS applications based on an image-guided approach involving the parallel synthesis and radiolabeling of a series of compounds based on the benzamide HDAC inhibitor, MS-275 as a template. BBB penetration was optimized by rapid carbon-11 labeling and PET imaging in the baboon model and using the imaging derived data on BBB penetration from each compound to feed back into the design process. A total of 17 compounds were evaluated, revealing molecules with both high binding affinity and BBB permeability. A key element conferring BBB penetration in this benzamide series was a basic benzylic amine. These derivatives exhibited 1-100 nM inhibitory activity against recombinant human HDAC1 and HDAC2. Three of the carbon-11 labeled aminomethyl benzamide derivatives showed high BBB penetration (?0.015%ID/cc) and regional binding heterogeneity in the brain (high in thalamus and cerebellum). Taken together this approach has afforded a strategy and a predictive model for developing highly potent and BBB permeable HDAC inhibitors for CNS applications and for the discovery of novel candidate molecules for small molecule probes and drugs. PMID:24780082

Seo, Young Jun; Kang, Yeona; Muench, Lisa; Reid, Alicia; Caesar, Shannon; Jean, Logan; Wagner, Florence; Holson, Edward; Haggarty, Stephen J; Weiss, Philipp; King, Payton; Carter, Pauline; Volkow, Nora D; Fowler, Joanna S; Hooker, Jacob M; Kim, Sung Won

2014-07-16

279

Class I and Class II Histone Deacetylases Are Potential Therapeutic Targets for Treating Pancreatic Cancer  

PubMed Central

Background Pancreatic cancer is a highly malignant disease with an extremely poor prognosis. Histone deacetylase inhibitors (HDACIs) have shown promising antitumor activities against preclinical models of pancreatic cancer, either alone or in combination with chemotherapeutic agents. In this study, we sought to identify clinically relevant histone deacetylases (HDACs) to guide the selection of HDAC inhibitors (HDACIs) tailored to the treatment of pancreatic cancer. Methodology HDAC expression in seven pancreatic cancer cell lines and normal human pancreatic ductal epithelial cells was determined by Western blotting. Antitumor interactions between class I- and class II-selective HDACIs were determined by MTT assays and standard isobologram/CompuSyn software analyses. The effects of HDACIs on cell death, apoptosis and cell cycle progression, and histone H4, alpha-tubulin, p21, and ?H2AX levels were determined by colony formation assays, flow cytometry analysis, and Western blotting, respectively. Results The majority of classes I and II HDACs were detected in the pancreatic cancer cell lines, albeit at variable levels. Treatments with MGCD0103 (a class I-selective HDACI) resulted in dose-dependent growth arrest, cell death/apoptosis, and cell cycle arrest in G2/M phase, accompanied by induction of p21 and DNA double-strand breaks (DSBs). In contrast, MC1568 (a class IIa-selective HDACI) or Tubastatin A (a HDAC6-selective inhibitor) showed minimal effects. When combined simultaneously, MC1568 significantly enhanced MGCD0103-induced growth arrest, cell death/apoptosis, and G2/M cell cycle arrest, while Tubastatin A only synergistically enhanced MGCD0103-induced growth arrest. Although MC1568 or Tubastatin A alone had no obvious effects on DNA DSBs and p21 expression, their combination with MGCD0103 resulted in cooperative induction of p21 in the cells. Conclusion Our results suggest that classes I and II HDACs are potential therapeutic targets for treating pancreatic cancer. Accordingly, treating pancreatic cancer with pan-HDACIs may be more beneficial than class- or isoform-selective inhibitors. PMID:23251689

Wang, Guan; He, Jing; Zhao, Jianyun; Yun, Wenting; Xie, Chengzhi; Taub, Jeffrey W.; Azmi, Asfar; Mohammad, Ramzi M.; Dong, Yan; Kong, Wei; Guo, Yingjie; Ge, Yubin

2012-01-01

280

Unliganded Thyroid Hormone Receptor Regulates Metamorphic Timing via the Recruitment of Histone Deacetylase Complexes  

PubMed Central

Anuran metamorphosis involves a complex series of tissue transformations that change an aquatic tadpole to a terrestrial frog and resembles the postembryonic perinatal period in mammals. Thyroid hormone (TH) plays a causative role in amphibian metamorphosis and its effect is mediated by TH receptors (TRs). Molecular analyses during Xenopus development have shown that unliganded TR recruits histone deacetylase (HDAC)-containing N-CoR/SMRT complexes and causes histone deacetylation at target genes while liganded TR leads to increased histone acetylations and altered histone methylations at target genes. Transgenic studies involving mutant TR-cofactors have shown that corepressor recruitment by unliganded TR is required to ensure proper timing of the onset of metamorphosis while coactivator levels influence the rate of metamorphic progression. In addition, a number of factors that can influence cellular free TH levels appear to contribute the timing of metamorphic transformations of different organs by regulating the levels of unliganded vs. liganded TR in an organ-specific manner. Thus, the recruitment of HDAC-containing corepressor complexes by unliganded TR likely controls both the timing of the initiation of metamorphosis and the temporal regulation of organ-specific transformations. Similar mechanisms likely mediate TR function in mammals as the maturation of many organs during postembryonic development is dependent upon TH and resembles organ metamorphosis in amphibians. PMID:23962846

2014-01-01

281

Histone deacetylase inhibition modulates cell fate decisions during myeloid differentiation  

PubMed Central

Background The clinical use of chromatin-modulating drugs, such as histone deacetylase inhibitors, for the treatment of bone marrow failure and hematopoietic malignancies has increased dramatically over the last few years. Nonetheless, little is currently known concerning their effects on myelopoiesis. Design and Methods We utilized an ex vivo differentiation system in which umbilical cord blood-derived CD34+ cells were treated with trichostatin A, sodium butyrate and valproic acid to evaluate the effect of histone deacetylase inhibitor treatment on myeloid lineage development, colony-forming potential, proliferation, and terminal neutrophil differentiation. Results Trichostatin A treatment modestly reduced progenitor proliferation, while sodium butyrate and valproic acid resulted in concentration-dependent effects on proliferation and apoptosis. Addition of valproic acid uniquely stimulated CD34+ proliferation. Sodium butyrate treatment inhibited terminal neutrophil differentiation both quantitatively and qualitatively. Addition of 100 ?M valproic acid resulted in increased numbers of mature neutrophils with a block in differentiation at increasing concentrations. Sodium butyrate and valproic acid treatment resulted in increased acetylation of histones 3 and 4 while trichostatin A, sodium butyrate and valproic acid had differential effects on the acetylation of non-histone proteins. Conclusions Individual histone deacetylase inihibitors had specific effects on cell fate decisions during myeloid development. These data provide novel insights into the effects of histone deacetylase inhibitors on the regulation of normal hematopoiesis, which is of importance when considering utilizing these compounds for the treatment of myeloid malignancies and bone marrow failure syndromes. PMID:20107159

Bartels, Marije; Geest, Christian R.; Bierings, Marc; Buitenhuis, Miranda; Coffer, Paul J.

2010-01-01

282

Histone Deacetylase 6 Inhibits Influenza A Virus Release by Downregulating the Trafficking of Viral Components to the Plasma Membrane via Its Substrate, Acetylated Microtubules  

PubMed Central

ABSTRACT Mammalian cells produce many proteins, such as IFITM3, ISG15, MxA, and viperin, that inhibit influenza A virus (IAV) infection. Here, we show that a new class of host protein, histone deacetylase 6 (HDAC6), inhibits IAV infection. We found that HDAC6-overexpressing cells release about 3-fold less IAV progeny, whereas HDAC6-depleted cells release about 6-fold more IAV progeny. The deacetylase activity of HDAC6 played a role in its anti-IAV function as tubacin, a specific small-molecule inhibitor of HDAC6, increased the release of IAV progeny in a dose-dependent manner. Further, as visualized by electron microscopy, tubacin-treated cells showed an increase in IAV budding at the plasma membrane, the site of IAV assembly. Tubacin is a domain-specific inhibitor and binds to one of the two HDAC6 catalytic domains possessing tubulin deacetylase activity. This indicated the potential involvement of acetylated microtubules in the trafficking of viral components to the plasma membrane. Indeed, as quantified by flow cytometry, there was about a 2.0- to 2.5-fold increase and about a 2.0-fold decrease in the amount of viral envelope protein hemagglutinin present on the plasma membrane of tubacin-treated/HDAC6-depleted and HDAC6-overexpressing cells, respectively. In addition, the viral ribonucleoprotein complex was colocalized with acetylated microtubule filaments, and viral nucleoprotein coimmunoprecipitated with acetylated tubulin. Together, our findings indicate that HDAC6 is an anti-IAV host factor and exerts its anti-IAV function by negatively regulating the trafficking of viral components to the host cell plasma membrane via its substrate, acetylated microtubules. IMPORTANCE Host cells produce many proteins that have the natural ability to restrict influenza virus infection. Here, we discovered that another host protein, histone deacetylase 6 (HDAC6), inhibits influenza virus infection. We demonstrate that HDAC6 exerts its anti-influenza virus function by negatively regulating the trafficking of viral components to the site of influenza virus assembly via its substrate, acetylated microtubules. HDAC6 is a multisubstrate enzyme and regulates multiple cellular pathways, including the ones leading to various cancers, neurodegenerative diseases, and inflammatory disorders. Therefore, several drugs targeting HDAC6 are under clinical development for the treatment of a wide range of diseases. Influenza virus continues to be a major global public health problem due to regular emergence of drug-resistant and novel influenza virus strains in humans. As an alternative antiviral strategy, HDAC6 modulators could be employed to stimulate the anti-influenza virus potential of endogenous HDAC6 to inhibit influenza virus infection. PMID:25031336

Cheung, Chen-Yi

2014-01-01

283

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

284

Deacetylase inhibitors - focus on non-histone targets and effects  

PubMed Central

Inhibitors of protein deacetylases have recently been established as a novel therapeutic principle for several human diseases, including cancer. The original notion of the mechanism of action of these compounds focused on the epigenetic control of transcriptional processes, especially of tumor suppressor genes, by interfering with the acetylation status of nuclear histone proteins, hence the name histone deacetylase inhibitors was coined. Yet, this view could not explain the high specificity for tumor cells and recent evidence now suggests that non-histone proteins represent major targets for protein deacetylase inhibitors and that the post-translational modification of the acetylome is involved in various cellular processes of differentiation, survival and cell death induction. PMID:21540990

Ocker, Matthias

2010-01-01

285

Dietary Regulation of Histone Acetylases and Deacetylases for the Prevention of Metabolic Diseases  

PubMed Central

Age-related diseases such as type 2 diabetes, cardiovascular disease, and cancer involve epigenetic modifications, where accumulation of minute changes in the epigenome over time leads to disease manifestation. Epigenetic changes are influenced by life style and diets. This represents an avenue whereby dietary components could accelerate or prevent age-related diseases through their effects on epigenetic modifications. Histone acetylation is an epigenetic modification that is regulated through the opposing action of histone acetylases (HATs) and deacetylases (HDACs). These two families of enzymes play critical roles in metabolic processes and their dysregulation is associated with pathogenesis of several diseases. Dietary components, such as butyrate, sulforaphane, and curcumin, have been shown to affect HAT and HDAC activity, and their health benefits are attributed, at least in part, to epigenetic modifications. Given the decades that it takes to accumulate epigenetic changes, it is unlikely that pharmaceuticals could undo epigenetic changes without side effects. Therefore, long term consumption of dietary components that can alter the epigenome could be an attractive means of disease prevention. The goal of this review is to highlight the roles of diets and food components in epigenetic modifications through the regulation of HATs and HDACs for disease prevention. PMID:23363995

Pham, Tho X.; Lee, Jiyoung

2012-01-01

286

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

287

Dietary regulation of histone acetylases and deacetylases for the prevention of metabolic diseases.  

PubMed

Age-related diseases such as type 2 diabetes, cardiovascular disease, and cancer involve epigenetic modifications, where accumulation of minute changes in the epigenome over time leads to disease manifestation. Epigenetic changes are influenced by life style and diets. This represents an avenue whereby dietary components could accelerate or prevent age-related diseases through their effects on epigenetic modifications. Histone acetylation is an epigenetic modification that is regulated through the opposing action of histone acetylases (HATs) and deacetylases (HDACs). These two families of enzymes play critical roles in metabolic processes and their dysregulation is associated with pathogenesis of several diseases. Dietary components, such as butyrate, sulforaphane, and curcumin, have been shown to affect HAT and HDAC activity, and their health benefits are attributed, at least in part, to epigenetic modifications. Given the decades that it takes to accumulate epigenetic changes, it is unlikely that pharmaceuticals could undo epigenetic changes without side effects. Therefore, long term consumption of dietary components that can alter the epigenome could be an attractive means of disease prevention. The goal of this review is to highlight the roles of diets and food components in epigenetic modifications through the regulation of HATs and HDACs for disease prevention. PMID:23363995

Pham, Tho X; Lee, Jiyoung

2012-12-01

288

Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, protects dopaminergic neurons from neurotoxin-induced damage  

PubMed Central

BACKGROUND AND PURPOSE Prevention or disease-modifying therapies are critical for the treatment of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease. However, no such intervention is currently available. Growing evidence has demonstrated that administration of histone deacetylase (HDAC) inhibitors ameliorates a wide range of neurologic and psychiatric disorders in experimental models. Suberoylanilide hydroxamic acid (SAHA) was the first HDAC inhibitor approved by the Food and Drug Administration for the sole use of cancer therapy. The purpose of this study was to explore the potential new indications of SAHA for therapy of neurodegenerative diseases in in vitro Parkinson's disease models. EXPERIMENTAL APPROACH Mesencephalic neuron–glia cultures and reconstituted cultures were used to investigate neurotrophic and neuroprotective effects of SAHA. We measured toxicity in dopaminergic neurons, using dopamine uptake assay and morphological analysis and expression of neurotrophic substances by enzyme-linked immunosorbent assay and real-time RT PCR. KEY RESULTS In mesencephalic neuron–glia cultures, SAHA displayed dose- and time-dependent prolongation of the survival and protection against neurotoxin-induced neuronal death of dopaminergic neurons. Mechanistic studies revealed that the neuroprotective effects of SAHA were mediated in part by promoting release of neurotrophic factors from astroglia through inhibition of histone deacetylation. CONCLUSION AND IMPLICATIONS The novel neurotrophic and neuroprotective effects of SAHA demonstrated in this study suggest that further study of this HDAC inhibitor could provide a new therapeutic approach to the treatment of neurodegenerative diseases. PMID:21726209

Chen, SH; Wu, HM; Ossola, B; Schendzielorz, N; Wilson, BC; Chu, CH; Chen, SL; Wang, Q; Zhang, D; Qian, L; Li, X; Hong, JS; Lu, RB

2012-01-01

289

Inhibition of Histone Deacetylases Facilitates Extinction and Attenuates Reinstatement of Nicotine Self-Administration in Rats  

PubMed Central

Chromatin remodelling is integral to the formation of long-term memories. Recent evidence suggests that histone modification may play a role in the persistence of memories associated with drug use. The present series of experiments aimed to examine the effect of histone deacetylase (HDAC) inhibition on the extinction and reinstatement of nicotine self-administration. Rats were trained to intravenously self-administer nicotine for 12 days on a fixed-ratio 1 schedule. In Experiment 1, responding was then extinguished through removal of nicotine and response-contingent cues. After each extinction session, the HDAC inhibitor, sodium butyrate (NaB), was administered immediately, or six hours after each session. In Experiment 2, response-contingent cues remained available across extinction to increase rates of responding during this phase, and NaB was administered immediately after the session. Finally, in Experiment 3, the effect of NaB treatment on extinction of responding for sucrose pellets was assessed. Across all experiments reinstatement to the cue and/or the reward itself was then tested. In the first experiment, treatment with NaB significantly attenuated nicotine and nicotine + cue reinstatement when administered immediately, but not six hours after each extinction session. When administered after cue-extinction (Expt. 2), NaB treatment specifically facilitated the rate of extinction across sessions, indicating that HDAC inhibition enhanced consolidation of the extinction memory. In contrast, there was no effect of NaB on the extinction and reinstatement of sucrose-seeking (Expt. 3), indicating that the observed effects are specific to a drug context. These results provide the first demonstration that HDAC inhibition facilitates the extinction of responding for an intravenously self-administered drug of abuse and further highlight the potential of HDAC inhibitors in the treatment of drug addiction. PMID:25880762

Castino, Matthew R.; Cornish, Jennifer L.; Clemens, Kelly J.

2015-01-01

290

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

291

Selective transcription and cellular proliferation induced by PDGF require histone deacetylase activity  

SciTech Connect

Histone deacetylases (HDACs) are key regulatory enzymes involved in the control of gene expression and their inhibition by specific drugs has been widely correlated to cell cycle arrest, terminal differentiation, and apoptosis. Here, we investigated whether HDAC activity was required for PDGF-dependent signal transduction and cellular proliferation. Exposure of PDGF-stimulated NIH3T3 fibroblasts to the HDAC inhibitor trichostatin A (TSA) potently repressed the expression of a group of genes correlated to PDGF-dependent cellular growth and pro-survival activity. Moreover, we show that TSA interfered with STAT3-dependent transcriptional activity induced by PDGF. Still, neither phosphorylation nor nuclear translocation and DNA-binding in vitro and in vivo of STAT3 were affected by using TSA to interfere with PDGF stimulation. Finally, TSA treatment resulted in the suppression of PDGF-dependent cellular proliferation without affecting cellular survival of NIH3T3 cells. Our data indicate that inhibition of HDAC activity antagonizes the mitogenic effect of PDGF, suggesting that these drugs may specifically act on the expression of STAT-dependent, PDGF-responsive genes.

Catania, Annunziata [Dipartimento di Biologia e Patologia Cellulare e Molecolare, Universita degli Studi di Napoli 'Federico II' (Italy); Iavarone, Carlo [Dipartimento di Biologia e Patologia Cellulare e Molecolare, Universita degli Studi di Napoli 'Federico II (Italy); Carlomagno, Stella M. [Dipartimento di Biologia e Patologia Cellulare e Molecolare, Universita degli Studi di Napoli 'Federico II' (Italy); Chiariello, Mario [Istituto di Endocrinologia e Oncologia Sperimentale, CNR, Via Pansini 5, 80131 Naples (Italy)]. E-mail: chiariel@unina.it

2006-05-05

292

Histone deacetylase 9 couples neuronal activity to muscle chromatin acetylation and gene expression.  

PubMed

Electrical activity arising from motor innervation influences skeletal muscle physiology by controlling the expression of many muscle genes, including those encoding acetylcholine receptor (AChR) subunits. How electrical activity is converted into a transcriptional response remains largely unknown. We show that motor innervation controls chromatin acetylation in skeletal muscle and that histone deacetylase 9 (HDAC9) is a signal-responsive transcriptional repressor which is downregulated upon denervation, with consequent upregulation of chromatin acetylation and AChR expression. Forced expression of Hdac9 in denervated muscle prevents upregulation of activity-dependent genes and chromatin acetylation by linking myocyte enhancer factor 2 (MEF2) and class I HDACs. By contrast, Hdac9-null mice are supersensitive to denervation-induced changes in gene expression and show chromatin hyperacetylation and delayed perinatal downregulation of myogenin, an activator of AChR genes. These findings show a molecular mechanism to account for the control of chromatin acetylation by presynaptic neurons and the activity-dependent regulation of skeletal muscle genes by motor innervation. PMID:15711539

Méjat, Alexandre; Ramond, Francis; Bassel-Duby, Rhonda; Khochbin, Saadi; Olson, Eric N; Schaeffer, Laurent

2005-03-01

293

Histone deacetylase inhibitors, valproic acid and trichostatin-A induce apoptosis and affect acetylation status of p53 in ERG-positive prostate cancer cells  

PubMed Central

An ETS family member, ETS Related Gene (ERG) is involved in the Ewing family of tumors as well as leukemias. Rearrangement of the ERG gene with the TMPRSS2 gene has been identified in the majority of prostate cancer patients. Additionally, overexpression of ERG is associated with un- favorable prognosis in prostate cancer patients similar to leukemia patients. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) regulate transcription as well as epigenetic status of genes through acetylation of both histones and transcription factors. Deregulation of HATs and HDACs is frequently seen in various cancers, including prostate cancer. Many cellular oncogenes as well as tumor viral proteins are known to target either or both HATs and HDACs. Several studies have demonstrated that there are alterations of HDAC activity in prostate cancer cells. Recently, we found that ERG binds and inhibits HATs, which suggests that ERG is involved in deregulation of protein acetylation. Additionally, it has been shown that ERG is associated with a higher expression of HDACs. In this study, we tested the effect of the HDAC inhibitors valproic acid (VPA) and trichostatin-A (TSA) on ERG-positive prostate cancer cells (VCaP). We found that VPA and TSA induce apoptosis, upregulate p21/Waf1/CIP1, repress TMPRSS2-ERG expression and affect acetylation status of p53 in VCaP cells. These results suggest that HDAC inhibitors might restore HAT activity through two different ways: by inhibiting HDAC activity and by repressing HAT targeting oncoproteins such as ERG. PMID:21519790

FORTSON, WENDELL S.; KAYARTHODI, SHUBHALAXMI; FUJIMURA, YASUO; XU, HUALI; MATTHEWS, ROLAND; GRIZZLE, WILLIAM E.; RAO, VEENA N.; BHAT, GANAPATHY K.; REDDY, E. SHYAM P.

2012-01-01

294

Expression of Latent HIV Induced by the Potent HDAC Inhibitor Suberoylanilide Hydroxamic Acid  

Microsoft Academic Search

Histone deacetylases (HDACs) act on histones within the nucleosome-bound promoter of human immunodefi- ciency virus type 1 (HIV-1) to maintain proviral latency. HDAC inhibition leads to promoter expression and the escape of HIV from latency. We evaluated the ability of the potent inhibitor recently licensed for use in oncology, suberoylanilide hydroxamic acid (SAHA; Vorinostat), selective for Class I HDACs, to

Nancie M. Archin; Amy Espeseth; Daniel Parker; Manzoor Cheema; Daria Hazuda; David M. Margolis

2009-01-01

295

Repeated treatment with electroconvulsive seizures induces HDAC2 expression and down-regulation of NMDA receptor-related genes through histone deacetylation in the rat frontal cortex.  

PubMed

The enzymatic activity of histone deacetylases (HDACs) leads to a histone deacetylation-mediated condensed chromatic structure, resulting in transcriptional repression, which has been implicated in the modifications of neural circuits and behaviors. Repeated treatment with electroconvulsive seizure (ECS) induces changes in histone acetylation, expression of various genes, and intrabrain cellular changes, including neurogenesis. In this study, we examined the effects of repeated ECS on the expression of class I HDACs and related changes in histone modifications and gene expression in the rat frontal cortex. Ten days of repeated ECS treatments (E10X) up-regulated HDAC2 expression at the mRNA and protein levels in the rat frontal cortex compared with sham-treated controls; this was evident in the nuclei of neuronal cells in the prefrontal, cingulate, orbital, and insular cortices. Among the known HDAC2 target genes, mRNA expression of N-methyl-d-aspartate (NMDA) receptor signaling-related genes, including early growth response-1 (Egr1), c-Fos, glutamate receptor, ionotropic, N-methyl d-aspartate 2A (Nr2a), Nr2b, neuritin1 (Nrn1), and calcium/calmodulin-dependent protein kinase II alpha (Camk2?), were decreased, and the histone acetylation of H3 and/or H4 proteins was also reduced by E10X. Chromatin immunoprecipitation analysis revealed that HDAC2 occupancy in the promoters of down-regulated genes was increased significantly. Moreover, administration of sodium butyrate, a HDAC inhibitor, during the course of E10X ameliorated the ECS-induced down-regulation of genes in the rat frontal cortex. These findings suggest that induction of HDAC2 by repeated ECS treatment could play an important role in the down-regulation of NMDA receptor signaling-related genes in the rat frontal cortex through histone modification. PMID:24606669

Park, Hong Geun; Yu, Hyun Sook; Park, Soyoung; Ahn, Yong Min; Kim, Yong Sik; Kim, Se Hyun

2014-09-01

296

A conserved histone deacetylase with a role in the regulation of cytokinesis in Schizosaccharomyces pombe  

PubMed Central

Background In Schizosaccharomyces pombe the SET domain protein, Set3p - together with its interacting partners, Snt1p, and Hif2p - form a complex that aids in preventing cell division failure upon mild cytokinetic stress. Intriguingly, the human orthologs of these proteins (MLL5, NCOR2, and TBL1X) are also important for the faithful completion of cytokinesis in tissue culture cells. Since MLL5, NCOR2, and TBL1X form a complex with the histone deacetylase, HDAC3, we sought to determine if an orthologous counterpart played a regulatory role in fission yeast cytokinesis. Results In this report we identify the hos2 gene as the fission yeast HDAC3 ortholog. We show that Hos2p physically interacts with Set3p, Snt1p, and Hif2p, and that hos2? mutants are indeed compromised in their ability to reliably complete cell division in the presence of mild cytokinetic stresses. Furthermore, we demonstrate that over-expression of hos2 causes severe morphological and cytokinetic defects. Lastly, through recombinase mediated cassette exchange, we show that expression of human HDAC3 complements the cytokinetic defects exhibited by hos2? cells. Conclusions These data support a model in which Hos2p functions as an essential component of the Set3p-Snt1p-Hif2p complex with respect to the regulation of cytokinesis. The ability of human HDAC3 to complement the cytokinesis defects associated with the deletion of the hos2 gene suggests that further analysis of this system could provide insight into the role of HDAC3 in both the regulation of cell division, as well as other biological processes influenced by HDAC3 deacetylation. PMID:22559741

2012-01-01

297

A novel role for histone deacetylase 6 in the regulation of the tolerogenic STAT3/IL-10 pathway in APCs.  

PubMed

APCs are critical in T cell activation and in the induction of T cell tolerance. Epigenetic modifications of specific genes in the APC play a key role in this process, and among them histone deacetylases (HDACs) have emerged as key participants. HDAC6, one of the members of this family of enzymes, has been shown to be involved in regulation of inflammatory and immune responses. In this study, to our knowledge we show for the first time that genetic or pharmacologic disruption of HDAC6 in macrophages and dendritic cells results in diminished production of the immunosuppressive cytokine IL-10 and induction of inflammatory APCs that effectively activate Ag-specific naive T cells and restore the responsiveness of anergic CD4(+) T cells. Mechanistically, we have found that HDAC6 forms a previously unknown molecular complex with STAT3, association that was detected in both the cytoplasmic and nuclear compartments of the APC. By using HDAC6 recombinant mutants we identified the domain comprising amino acids 503-840 as being required for HDAC6 interaction with STAT3. Furthermore, by re-chromatin immunoprecipitation we confirmed that HDAC6 and STAT3 are both recruited to the same DNA sequence within the Il10 gene promoter. Of note, disruption of this complex by knocking down HDAC6 resulted in decreased STAT3 phosphorylation--but no changes in STAT3 acetylation--as well as diminished recruitment of STAT3 to the Il10 gene promoter region. The additional demonstration that a selective HDAC6 inhibitor disrupts this STAT3/IL-10 tolerogenic axis points to HDAC6 as a novel molecular target in APCs to overcome immune tolerance and tips the balance toward T cell immunity. PMID:25108026

Cheng, Fengdong; Lienlaf, Maritza; Wang, Hong-Wei; Perez-Villarroel, Patricio; Lee, Calvin; Woan, Karrune; Rock-Klotz, Jennifer; Sahakian, Eva; Woods, David; Pinilla-Ibarz, Javier; Kalin, Jay; Tao, Jianguo; Hancock, Wayne; Kozikowski, Alan; Seto, Edward; Villagra, Alejandro; Sotomayor, Eduardo M

2014-09-15

298

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

299

LSD1 Regulates Pluripotency of Embryonic Stem/Carcinoma Cells through Histone Deacetylase 1-Mediated Deacetylation of Histone H4 at Lysine 16  

PubMed Central

LSD1 is essential for the maintenance of pluripotency of embryonic stem (ES) or embryonic carcinoma/teratocarcinoma (EC) cells. We have previously developed novel LSD1 inhibitors that selectively inhibit ES/EC cells. However, the critical targets of LSD1 remain unclear. Here, we found that LSD1 interacts with histone deacetylase 1 (HDAC1) to regulate the proliferation of ES/EC cells through acetylation of histone H4 at lysine 16 (H4K16), which we show is a critical substrate of HDAC1. The LSD1 demethylase and HDAC1 deacetylase activities were both inactivated if one of them in the complex was chemically inhibited in ES/EC cells or in reconstituted protein complexes. Loss of HDAC1 phenocopied the selective growth-inhibitory effects and increased the levels of H3K4 methylation and H4K16 acetylation of LSD1 inactivation on ES/EC cells. Reduction of acetylated H4K16 by ablation of the acetyltransferase males absent on the first (MOF) is sufficient to rescue the growth inhibition induced by LSD1 inactivation. While LSD1 or HDAC1 inactivation caused the downregulation of Sox2 and Oct4 and induction of differentiation genes, such as FOXA2 or BMP2, depletion of MOF restored the levels of Sox2, Oct4, and FoxA2 in LSD1-deficient cells. Our studies reveal a novel mechanism by which LSD1 acts through the HDAC1- and MOF-mediated regulation of H4K16 acetylation to maintain the pluripotency of ES/EC cells. PMID:24190971

Yin, Feng; Lan, Rongfeng; Zhang, Xiaoming; Zhu, Linyu; Chen, Fangfang; Xu, Zhengshuang; Liu, Yuqing; Ye, Tao; Sun, Hong

2014-01-01

300

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

301

Histone deacetylase inhibitors as therapeutics for polyglutamine disorders  

Microsoft Academic Search

During the past 5 years, gene expression studies in cell culture, animal models and in the brains of patients have shown that the perturbation of transcription frequently results in neuronal dysfunction in polyglutamine repeat diseases such as Huntington's disease. Histone deacetylases act as repressors of transcription through interactions with co-repressor complexes, which leads to chromatin remodelling. Aberrant interactions between polyglutamine

Rachel Butler; Gillian P. Bates

2006-01-01

302

HdaA, a class 2 histone deacetylase of Aspergillus fumigatus, affects germination and secondary metabolite production  

PubMed Central

Histone deacetylases (HDACs) play an important role in regulation of gene expression through histone modifications. Here we show that the Aspergillus fumigatus HDAC HdaA is involved in regulation of secondary metabolite production and is required for normal germination and vegetative growth. Deletion of the hdaA gene increased the production of several secondary metabolites but decreased production of gliotoxin whereas over-expression hdaA increased production of gliotoxin. RT-PCR analysis of 14 non-ribosomal peptide synthases indicated HdaA regulation of up to 9 of them. A mammalian cell toxicity assay indicated increased activity in the over-expression strain. Neither mutant affected virulence of the fungus as measured by macrophage engulfment of conidia or virulence in a neutropenic mouse model. PMID:19563902

Lee, Inhyung; Oh, Jee-Hwan; Shwab, E. Keats; Dagenais, Taylor R. T.; Andes, David; Keller, Nancy P.

2009-01-01

303

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

304

mTOR kinase inhibitors synergize with histone deacetylase inhibitors to kill B-cell acute lymphoblastic leukemia cells  

PubMed Central

High activity of the mechanistic target of rapamycin (mTOR) is associated with poor prognosis in pre-B-cell acute lymphoblastic leukemia (B-ALL), suggesting that inhibiting mTOR might be clinically useful. However, emerging data indicate that mTOR inhibitors are most effective when combined with other target agents. One strategy is to combine with histone deacetylase (HDAC) inhibitors, since B-ALL is often characterized by epigenetic changes that silence the expression of pro-apoptotic factors. Here we tested combinations of mTOR and pan-HDAC inhibitors on B-ALL cells, including both Philadelphia chromosome-positive (Ph+) and non-Ph cell lines. We found that mTOR kinase inhibitors (TOR-KIs) synergize with HDAC inhibitors to cause apoptosis in B-ALL cells and the effect is greater when compared to rapamycin plus HDAC inhibitors. The combination of TOR-KIs with the clinically approved HDAC inhibitor vorinostat increased apoptosis in primary pediatric B-ALL cells in vitro. Mechanistically, TOR-KI and HDAC inhibitor combinations increased expression of pro-death genes, including targets of the Forkhead Box O (FOXO) transcription factors, and increased sensitivity to apoptotic triggers at the mitochondria. These findings suggest that targeting epigenetic factors can unmask the cytotoxic potential of TOR-KIs towards B-ALL cells. PMID:25576920

Beagle, Brandon R.; Nguyen, Duc M.; Mallya, Sharmila; Tang, Sarah S.; Lu, Mengrou; Zeng, Zhihong; Konopleva, Marina; Vo, Thanh-Trang; Fruman, David A.

2015-01-01

305

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

306

Curcumin and hydroxamate-derivative (PCI-34058) interfere with histone deacetylase I catalytic core Asp-His charge relay system: atomistic simulation studies.  

PubMed

Histone deacetylases (HDACs) are representative targets for the natural and synthetic chemicals used to transform cells to confer antitumor properties. In the current study, curcumin and hydroxamate-derivative PCI-34058-bound HDAC1 were subjected to atomistic simulation. The results support the view that fitting of curcumin and PCI-34058 within the HDAC1 pocket depends on extensive interactions between the aromatic moieties of the inhibitors and the extensive network of aromatic amino acid side chains lining the pocket of HDAC1. The interaction forces a local perturbation of the coiled structures connecting the pocket residues resulting in ligand-induced tightening of the pocket. In addition to the competitive occupancy of the histone-acetyl-lysine binding pocket by the inhibitors, interference with the in-pocket aspartate-histidine (ASP-HIS) charge relay system was also observed in inhibitor-bound HDAC1 systems. In conclusion, curcumin and PCI-34058-mediated ligand-dependent HDAC1 tunnel closure interferes negatively with the ASP-HIS charge relay system in HDAC1. Future design of HDAC inhibitors may benefit from optimizing competitive interaction with the ligand site and interference with the charge relay system. PMID:25860111

Omotuyi, I O; Abiodun, M O; Komolafe, K; Ejelonu, O C; Olusanya, O

2015-05-01

307

The coactivator role of histone deacetylase 3 in IL-1-signaling involves deacetylation of p65 NF-?B  

PubMed Central

Histone deacetylase (HDAC) 3, as a cofactor in co-repressor complexes containing silencing mediator for retinoid or thyroid-hormone receptors (SMRT) and nuclear receptor co-repressor (N-CoR), has been shown to repress gene transcription in a variety of contexts. Here, we reveal a novel role for HDAC3 as a positive regulator of IL-1-induced gene expression. Various experimental approaches involving RNAi-mediated knockdown, conditional gene deletion or small molecule inhibitors indicate a positive role of HDAC3 for transcription of the majority of IL-1-induced human or murine genes. This effect was independent from the gene regulatory effects mediated by the broad-spectrum HDAC inhibitor trichostatin A (TSA) and thus suggests IL-1-specific functions for HDAC3. The stimulatory function of HDAC3 for inflammatory gene expression involves a mechanism that uses binding to NF-?B p65 and its deacetylation at various lysines. NF-?B p65-deficient cells stably reconstituted to express acetylation mimicking forms of p65 (p65 K/Q) had largely lost their potential to stimulate IL-1-triggered gene expression, implying that the co-activating property of HDAC3 involves the removal of inhibitory NF-?B p65 acetylations at K122, 123, 314 and 315. These data describe a novel function for HDAC3 as a co-activator in inflammatory signaling pathways and help to explain the anti-inflammatory effects frequently observed for HDAC inhibitors in (pre)clinical use. PMID:23087373

Ziesché, Elisabeth; Kettner-Buhrow, Daniela; Weber, Axel; Wittwer, Tobias; Jurida, Liane; Soelch, Johanna; Müller, Helmut; Newel, Doris; Kronich, Petra; Schneider, Heike; Dittrich-Breiholz, Oliver; Bhaskara, Srividya; Hiebert, Scott W.; Hottiger, Michael O.; Li, Haiying; Burstein, Ezra; Schmitz, M. Lienhard; Kracht, Michael

2013-01-01

308

Inhibition of Histone Deacetylase Impacts Cancer Stem Cells and Induces Epithelial-Mesenchyme Transition of Head and Neck Cancer  

PubMed Central

The genome is organized and packed into the nucleus through interactions with core histone proteins. Emerging evidence suggests that tumors are highly responsive to epigenetic alterations that induce chromatin-based events and dynamically influence tumor behavior. We examined chromatin organization in head and neck squamous cell carcinoma (HNSCC) using acetylation levels of histone 3 as a marker of chromatin compaction. Compared to control oral keratinocytes, we found that HNSCC cells are hypoacetylated and that microenvironmental cues (e.g., microvasculature endothelial cells) induce tumor acetylation. Furthermore, we found that chemical inhibition of histone deacetylases (HDAC) reduces the number of cancer stem cells (CSC) and inhibits clonogenic sphere formation. Paradoxically, inhibition of HDAC also induced epithelial-mesenchymal transition (EMT) in HNSCC cells, accumulation of BMI-1, an oncogene associated with tumor aggressiveness, and expression of the vimentin mesenchymal marker. Importantly, we observed co-expression of vimentin and acetylated histone 3 at the invasion front of human HNSCC tumor tissues. Collectively, these findings suggest that environmental cues, such as endothelial cell-secreted factors, modulate tumor plasticity by limiting the population of CSC and inducing EMT. Therefore, inhibition of HDAC may constitute a novel strategy to disrupt the population of CSC in head and neck tumors to create a homogeneous population of cancer cells with biologically defined signatures and predictable behavior. PMID:23527004

Giudice, Fernanda S.; Pinto, Decio S.; Nör, Jacques E.; Squarize, Cristiane H.; Castilho, Rogerio M.

2013-01-01

309

Histone Deacetylase Inhibition Attenuates Cardiac Hypertrophy and Fibrosis through Acetylation of Mineralocorticoid Receptor in Spontaneously Hypertensive Rats.  

PubMed

Inhibition of histone deacetylases (HDACs) by valproic acid (VPA) attenuates inflammatory, hypertrophic, and fibrotic responses in the hearts of spontaneously hypertensive rats (SHRs); however, the molecular mechanism is still unclear. We hypothesized that HDAC inhibition (HDACi) attenuates cardiac hypertrophy and fibrosis through acetylation of mineralocorticoid receptor (MR) in SHRs. Seven-week-old SHRs and Wistar-Kyoto rats were treated with an HDAC class I inhibitor (0.71% w/v in drinking water; VPA) for 11 weeks. Sections of heart were visualized after trichrome stain as well as H&E stain. Histone modifications, such as acetylation (H3Ac [acetylated histone 3]) and fourth lysine trimethylation (H3K4me3) of histone 3, and recruitment of MR and RNA polymerase II (Pol II) into promoters of target genes were measured by quantitative real-time polymerase chain reaction after chromatin immunoprecipitation assay. MR acetylation was determined by Western blot with anti-acetyl-lysine antibody after immunoprecipitation with anti-MR antibody. Treatment with VPA attenuated cardiac hypertrophy and fibrosis. Although treatment with VPA increased H3Ac and H3K4me3 on promoter regions of MR target genes, expression of MR target genes as well as recruitment of MR and Pol II on promoters of target genes were decreased. Although HDACi did not affect MR expression, it increased MR acetylation. These results indicate that HDACi attenuates cardiac hypertrophy and fibrosis through acetylation of MR in spontaneously hypertensive rats. PMID:25667225

Kang, Seol-Hee; Seok, Young Mi; Song, Min-Ji; Lee, Hae-Ahm; Kurz, Thomas; Kim, InKyeom

2015-05-01

310

NAD+-dependent deacetylation of H4 lysine 16 by class III HDACs  

Microsoft Academic Search

Histone deacetylases (HDACs) catalyse the removal of acetyl groups from the N-terminal tails of histones. All known HDACs can be categorized into one of four classes (I–IV). The class III HDAC or silencing information regulator 2 (Sir2) family exhibits characteristics consistent with a distinctive role in regulation of chromatin structure. Accumulating data suggest that these deacetylases acquired new roles as

A Vaquero; R Sternglanz; D Reinberg

2007-01-01

311

Enhanced deacetylation of p53 by the anti-apoptotic protein HSCO in association with histone deacetylase 1.  

PubMed

HSCO (hepatoma subtracted-cDNA library clone one, also called ETHE1) was originally identified by its frequent overexpression in hepatocellular carcinomas. HSCO inhibits function of NF-kappaB by binding to RelA and accelerating its export from the nucleus. We show here that HSCO exhibits anti-apoptotic activity in cells exposed to DNA-damaging agents by suppressing transcriptional activity of p53. Induction of pro-apoptotic genes, Noxa, Perp, PIG3, and Bax were suppressed in cells over-expressing HSCO. By increasing ubiquitylation and degradation of p53, HSCO reduces p53 protein levels. HSCO specifically associates with histone deacetylase 1 (HDAC1) independently of Mdm2 and facilitates deacetylation of p53 at Lys-373/382 by HDAC1. The metallo-beta-lactamase family consensus sequence in HSCO is important for its effect on p53 deacetylation. Co-immunoprecipitation and immunofluorescence studies suggested that HSCO, HDAC1, and p53 form a complex in the nucleus. Thus, HSCO is a cofactor that increases the deacetylase activity of HDAC1 toward p53, leading to suppression of apoptosis. Treatment of hepatocellular carcinomas that retain wild-type p53 and overexpress HSCO with anti-HSCO agents might re-establish the p53 response and revert chemoresistance. PMID:17353187

Higashitsuji, Hisako; Higashitsuji, Hiroaki; Masuda, Tomoko; Liu, Yu; Itoh, Katsuhiko; Fujita, Jun

2007-05-01

312

Incorporation of histone deacetylase inhibition into the structure of a nuclear receptor agonist  

PubMed Central

1,25-dihydroxyvitamin D3 (1,25D) regulates gene expression by signaling through the nuclear vitamin D receptor (VDR) transcription factor and exhibits calcium homeostatic, anticancer, and immunomodulatory properties. Histone deacetylase inhibitors (HDACis) alter nuclear and cytoplasmic protein acetylation, modify gene expression, and have potential for treatment of cancer and other indications. The function of nuclear receptor ligands, including 1,25D, can be enhanced in combination with HDACi. We designed triciferol, a hybrid molecule in which the 1,25D side chain was replaced with the dienyl hydroxamic acid of HDACi trichostatin A. Triciferol binds directly to the VDR, and functions as an agonist with 1,25D-like potency on several 1,25D target genes. Moreover, unlike 1,25D, triciferol induces marked tubulin hyperacetylation, and augments histone acetylation at concentrations that largely overlap those where VDR agonism is observed. Triciferol also exhibits more efficacious antiproliferative and cytotoxic activities than 1,25D in four cancer cell models in vitro. The bifunctionality of triciferol is notable because (i) the HDACi activity is generated by modifying the 1,25D side chain without resorting to linker technology and (ii) 1,25D and HDACi have sympathetic, but very distinct biochemical targets; the hydrophobic VDR ligand binding domain and the active sites of HDACs, which are zinc metalloenzymes. These studies demonstrate the feasibility of combining HDAC inhibition with nuclear receptor agonism to enhance their therapeutic potential. PMID:18550844

Tavera-Mendoza, Luz E.; Quach, Tan D.; Dabbas, Basel; Hudon, Jonathan; Liao, Xiaohong; Palijan, Ana; Gleason, James L.; White, John H.

2008-01-01

313

Treadmill exercise alters histone acetyltransferases and histone deacetylases activities in frontal cortices from wistar rats.  

PubMed

Studies have pointed out the relationship between neuroprotective exercise effects and epigenetic mechanisms on the hippocampus. Considering the role of frontal cortex on brain functions, we investigated the impact of different exercise protocols on enzymatic system involved with histone acetylation status, histone acetyltransferases (HATs), and histone desacetylases (HDACs) in frontal cortices from Wistar rats. Male Wistar rats aged 3 months were submitted to a single session or a daily running protocol during 2 weeks. The single session enhanced HAT activity, while the moderate daily exercise protocol reduced the HDAC activity. Our results indicate that frontal cortex is susceptible to epigenetic modulation following exercise and that both exercise protocols seem to induce a histone hyperacetylation condition in this brain area. PMID:25149076

Spindler, Christiano; Cechinel, Laura Reck; Basso, Carla; Moysés, Felipe; Bertoldi, Karine; Roesler, Rafael; Lovatel, Gisele Agustini; Rostirola Elsner, Viviane; Siqueira, Ionara Rodrigues

2014-11-01

314

Gene Expression Mapping of Histone Deacetylases and Co-factors, and Correlation with Survival Time and (1)H-HRMAS Metabolomic Profile in Human Gliomas.  

PubMed

Primary brain tumors are presently classified based on imaging and histopathological techniques, which remains unsatisfaying. We profiled here by quantitative real time PCR (qRT-PCR) the transcripts of eighteen histone deacetylases (HDACs) and a subset of transcriptional co-factors in non-tumoral brain samples from 15 patients operated for epilepsia and in brain tumor samples from 50 patients diagnosed with grade II oligodendrogliomas (ODII, n = 9), grade III oligodendrogliomas (ODIII, n = 22) and glioblastomas (GL, n = 19). Co-factor transcripts were significantly different in tumors as compared to non-tumoral samples and distinguished different molecular subgroups of brain tumors, regardless of tumor grade. Among all patients studied, the expression of HDAC1 and HDAC3 was inversely correlated with survival, whereas the expression of HDAC4, HDAC5, HDAC6, HDAC11 and SIRT1 was significantly and positively correlated with survival time of patients with gliomas. (1)H-HRMAS technology revealed metabolomically distinct groups according to the expression of HDAC1, HDAC4 and SIRT1, suggesting that these genes may play an important role in regulating brain tumorigenesis and cancer progression. Our study hence identified different molecular fingerprints for subgroups of histopathologically similar brain tumors that may enable the prediction of outcome based on the expression level of co-factor genes and could allow customization of treatment. PMID:25791281

Dali-Youcef, Nassim; Froelich, Sébastien; Moussallieh, François-Marie; Chibbaro, Salvatore; Noël, Georges; Namer, Izzie J; Heikkinen, Sami; Auwerx, Johan

2015-01-01

315

Gene Expression Mapping of Histone Deacetylases and Co-factors, and Correlation with Survival Time and 1H-HRMAS Metabolomic Profile in Human Gliomas  

PubMed Central

Primary brain tumors are presently classified based on imaging and histopathological techniques, which remains unsatisfaying. We profiled here by quantitative real time PCR (qRT-PCR) the transcripts of eighteen histone deacetylases (HDACs) and a subset of transcriptional co-factors in non-tumoral brain samples from 15 patients operated for epilepsia and in brain tumor samples from 50 patients diagnosed with grade II oligodendrogliomas (ODII, n = 9), grade III oligodendrogliomas (ODIII, n = 22) and glioblastomas (GL, n = 19). Co-factor transcripts were significantly different in tumors as compared to non-tumoral samples and distinguished different molecular subgroups of brain tumors, regardless of tumor grade. Among all patients studied, the expression of HDAC1 and HDAC3 was inversely correlated with survival, whereas the expression of HDAC4, HDAC5, HDAC6, HDAC11 and SIRT1 was significantly and positively correlated with survival time of patients with gliomas. 1H-HRMAS technology revealed metabolomically distinct groups according to the expression of HDAC1, HDAC4 and SIRT1, suggesting that these genes may play an important role in regulating brain tumorigenesis and cancer progression. Our study hence identified different molecular fingerprints for subgroups of histopathologically similar brain tumors that may enable the prediction of outcome based on the expression level of co-factor genes and could allow customization of treatment. PMID:25791281

Dali-Youcef, Nassim; Froelich, Sébastien; Moussallieh, François-Marie; Chibbaro, Salvatore; Noël, Georges; Namer, Izzie J.; Heikkinen, Sami; Auwerx, Johan

2015-01-01

316

With NuRD, HDACs Go "Nerdy".  

PubMed

Reporting in a recent issue of Neuron, Yamada et al. (2014) show that the histone deacetylase (HDAC)-containing NuRD complex plays a critical role in shutting down expression of specific synaptogenesis-related genes in the cerebellum, resulting in enhanced differentiation of presynaptic structures. This work suggests that HDACs in neurons acquire specificity through NuRD. PMID:25026033

Sun, Yi Eve; Cheng, Liming; Hu, Keping

2014-07-14

317

Largazole and Analogues with Modified Metal-Binding Motifs Targeting Histone Deacetylases: Synthesis and Biological Evaluation  

PubMed Central

The histone deacetylase inhibitor, largazole 1 was synthesized by a convergent approach which involved several efficient and high yielding single pot multistep protocols. Initial attempts using t-butyl as thiol protecting group proved problematic and synthesis was accomplished by switching to trityl protecting group. This synthetic protocol provides a convenient approach to many new largazole analogues. Three side chain analogues with multiple heteroatoms for chelation with Zn2+ were synthesized and their biological activities were evaluated. They were less potent than largazole 1 in growth inhibition of HCT116 colon carcinoma cell line and in inducing increases in global H3 acetylation. Largazole 1 and the three side chain analogues had no effect on HDAC6 as indicated by the lack of increased acetylation of ?-tubulin. PMID:21936551

Bhansali, Pravin; Hanigan, Christin L.; Casero, Robert A.; Tillekeratne, L. M. Viranga

2011-01-01

318

Targeting AML1\\/ETO-Histone Deacetylase Repressor Complex: A Novel Mechanism for Valproic Acid-Mediated Gene Expression and Cellular Differentiation in AML1\\/ETO-Positive Acute Myeloid Leukemia Cells  

Microsoft Academic Search

In t(8;21) acute myeloid leukemia (AML), the AML1\\/ETO fusion protein promotes leukemogenesis by recruiting class I histone deacetylase (HDAC)-containing repressor complex to the pro- moter of AML1 target genes. Valproic acid (VPA), a commonly used antiseizure and mood stabilizer drug, has been shown to cause growth arrest and induce differentiation of malignant cells via HDAC inhibition. VPA causes selective proteasomal

Shujun Liu; Rebecca B. Klisovic; Tamara Vukosavljevic; Jianhua Yu; Peter Paschka; Lenguyen Huynh; Jiuxia Pang; Paolo Neviani; Zhongfa Liu; William Blum; Kenneth K. Chan; Danilo Perrotti; Guido Marcucci

2007-01-01

319

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

320

Loss of deacetylation activity of Hdac6 affects emotional behavior in mice.  

PubMed

Acetylation is mediated by acetyltransferases and deacetylases, and occurs not only on histones but also on diverse proteins. Although histone acetylation in chromatin structure and transcription has been well studied, the biological roles of non-histone acetylation remain elusive. Histone deacetylase 6 (Hdac6), a member of the histone deacetylase (HDAC) family, is a unique deacetylase that localizes to cytoplasm and functions in many cellular events by deacetylating non-histone proteins including ?-tubulin, Hsp90, and cortactin. Since robust expression of Hdac6 is observed in brain, it would be expected that Hdac6-mediated reversible acetylation plays essential roles in CNS. Here we demonstrate the crucial roles of Hdac6 deacetylase activity in the expression of emotional behavior in mice. We found that Hdac6-deficient mice exhibit hyperactivity, less anxiety, and antidepressant-like behavior in behavioral tests. Moreover, administration of Hdac6-specific inhibitor replicated antidepressant-like behavior in mice. In good agreement with behavioral phenotypes of Hdac6-deficient mice, Hdac6 dominantly localizes to the dorsal and median raphe nuclei, which are involved in emotional behaviors. These findings suggest that HDAC6-mediated reversible acetylation might contribute to maintain proper neuronal activity in serotonergic neurons, and also provide a new therapeutic target for depression. PMID:22328923

Fukada, Masahide; Hanai, Atsuko; Nakayama, Atsuo; Suzuki, Takayoshi; Miyata, Naoki; Rodriguiz, Ramona M; Wetsel, William C; Yao, Tso-Pang; Kawaguchi, Yoshiharu

2012-01-01

321

Effect of histone deacetylase inhibitor sodium butyrate (NaB) on transformants E1a+cHa-Ras expressing wild type p53 with suppressed transactivation function  

Microsoft Academic Search

The induction of cellular senescence by various antitumor agents is a promising strategy of cancer treatment. We assessed\\u000a the ability of sodium butyrate (NaB), a histone deacetylase inhibitor (HDAC), to reactivate the cellular senescence program\\u000a in the E1A+cHa-Ras-transformed rat embryo fibroblasts with wild-type p53 (ERasWT) and in the isogenic cell line, where p53 is inactivated due to expression of the

E. I. Bukreeva; N. D. Aksenov; A. A. Bardin; V. A. Pospelov; T. V. Pospelova

2009-01-01

322

Inhibitors of Histone Deacetylase and DNA Methyltransferase Synergistically Activate the Methylated Metallothionein I Promoter by Activating the Transcription Factor MTF1 and Forming an Open Chromatin Structure  

Microsoft Academic Search

Inhibitors of DNA methyltransferase (Dnmt) and histone deacetylases (HDAC) synergistically activate the methylated metallothionein I gene (MT-I) promoter in mouse lymphosarcoma cells. The cooperative effect of these two classes of inhibitors on MT-I promoter activity was robust following demethylation of only a few CpG dinucleotides by brief exposure to 5-azacytidine (5-AzaC) but persisted even after prolonged treatment with the nucleoside

Kalpana Ghoshal; Jharna Datta; Sarmila Majumder; Shoumei Bai; Xiaocheng Dong; Mark Parthun; Samson T. Jacob

2002-01-01

323

Release of Methyl CpG Binding Proteins and Histone Deacetylase 1 from the Estrogen Receptor (ER) Promoter upon Reactivation in ER-Negative Human Breast Cancer Cells  

Microsoft Academic Search

Estrogen receptor (ER) is an epigenetically reg- ulated gene. Inhibitors of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) syner- gistically activate the methylated ER gene pro- moter in ER-negative MDA-MB-231 human breast cancer cells. Chromatin immunoprecipitation was used to examine the chromatin status and repres- sor complex associated with silenced ER and changes in the key regulatory factors during reac-

Dipali Sharma; Julie Blum; Normand Beaulieu; A. Robert Macleod; Nancy E. Davidson

2000-01-01

324

Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes  

PubMed Central

Histone acetyltransferases (HATs) and histone deacetylases (HDACs) function antagonistically to control histone acetylation states that are crucial to many cellular processes. We describe here genome-wide mapping experiments that reveal that both HATs (CBP, p300, PCAF, Tip60, MOF) and HDACs (HDAC1, HDAC2, HDAC3, HDAC6) on chromatin are positively correlated with gene expression and histone acetylation. We provide evidence that Tip60 and HDAC6 are targeted to transcribed regions of active genes by phosphorylated RNA Pol II. Our results indicate that MLL-mediated H3K4 methylation primes chromatin to facilitate histone acetylation. Our data suggest that the majority of HDACs in the human genome function to reset chromatin by removing acetylation in active genes; the dynamic cycle of acetylation and deacetylation by transient HAT/HDAC binding prevents Pol II from binding to the genes primed by H3K4 methylation and poises them for future activation. PMID:19698979

Wang, Zhibin; Zang, Chongzhi; Cui, Kairong; Schones, Dustin E.; Barski, Artem; Peng, Weiqun; Zhao, Keji

2009-01-01

325

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

326

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

327

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

328

Structure-function analysis of the conserved tyrosine and diverse ?-stacking among class I histone deacetylases: a QM (DFT)/MM MD study.  

PubMed

Discovery of the isoform-selective histone deacetylases (HDACs) inhibitors is of great medical importance and still a challenge. The comparison studies on the structure-function relationship of the conserved residues, which are located in the linker binding channel among class I HDACs (including 4 isoforms: HDAC1/2/3/8), have been carried out by using ab initio QM/MM MD simulations, a state-of-the-art approach to simulate metallo-enzymes. We found that the conserved tyrosine (Y303/308/286/306 in HDAC1/2/3/8, respectively) could modulate the zinc-inhibitor chelation among all class I HDACs with different regulatory mechanisms. For HDAC1/2/3 selective-inhibitor benzamide, the conserved tyrosine could modulate the coordinative ability of the central atom (Zn(2+)), while for pan-inhibitor SAHA, the conserved tyrosine could increase the chelating ability of the ligand (SAHA). Moreover, it is first found that the conserved tyrosine is correlated with the intertransformation of ?-? stacking styles (parallel shift vs T-shaped) by the aromatic ring in benzamide and the two conserved phenylalanine residues of HDACs. In addition, the catalytic roles of the conserved tyrosine in stabilizing the transition state and intermediate are further revealed. These findings provide useful molecular basis knowledge for further isoform-selective inhibitor design among class I HDACs. PMID:25360823

Zhou, Jingwei; Xie, Hujun; Liu, Zhihong; Luo, Hai-Bin; Wu, Ruibo

2014-11-24

329

Phosphoproteomic analysis reveals an intrinsic pathway for histone deacetylase 7 regulation that controls cytotoxic T lymphocyte function  

PubMed Central

The present study reports an unbiased analysis of cytotoxic T cell serine-threonine phosphoproteome using high resolution mass spectrometry. Approximately 2,000 phosphorylations were identified in CTLs of which approximately 450 were controlled by TCR signaling. A significantly overrepresented group of molecules identified were transcription activators, co-repressors and chromatin regulators. A focus on chromatin regulators revealed that CTLs have high expression of histone deacetylase HDAC7 but continually phosphorylate and export this transcriptional repressor from the nucleus. HDAC7 dephosphorylation results in its nuclear accumulation and suppressed expression of genes encoding key cytokines, cytokine receptors and adhesion molecules that determine CTL function. The screening of CTL phosphoproteome thus reveals intrinsic pathways of serine-threonine phosphorylation that target chromatin regulators and determine the CTL functional program. PMID:21399638

Navarro, Maria N.; Goebel, Jurgen; Feijoo-Carnero, Carmen; Morrice, Nick; Cantrell, Doreen A.

2011-01-01

330

Inhibition of HDAC6 deacetylase activity increases its binding with microtubules and suppresses microtubule dynamic instability in MCF-7 cells.  

PubMed

The post-translational modification of tubulin appears to be a highly controlled mechanism that regulates microtubule functioning. Acetylation of the ?-amino group of Lys-40 of ?-tubulin marks stable microtubules, although the causal relationship between tubulin acetylation and microtubule stability has remained poorly understood. HDAC6, the tubulin deacetylase, plays a key role in maintaining typical distribution of acetylated microtubules in cells. Here, by using tubastatin A, an HDAC6-specific inhibitor, and siRNA-mediated depletion of HDAC6, we have explored whether tubulin acetylation has a role in regulating microtubule stability. We found that whereas both pharmacological inhibition of HDAC6 as well as its depletion enhance microtubule acetylation, only pharmacological inhibition of HDAC6 activity leads to an increase in microtubule stability against cold and nocodazole-induced depolymerizing conditions. Tubastatin A treatment suppressed the dynamics of individual microtubules in MCF-7 cells and delayed the reassembly of depolymerized microtubules. Interestingly, both the localization of HDAC6 on microtubules and the amount of HDAC6 associated with polymeric fraction of tubulin were found to increase in the tubastatin A-treated cells compared with the control cells, suggesting that the pharmacological inhibition of HDAC6 enhances the binding of HDAC6 to microtubules. The evidence presented in this study indicated that the increased binding of HDAC6, rather than the acetylation per se, causes microtubule stability. The results are in support of a hypothesis that in addition to its deacetylase function, HDAC6 might function as a MAP that regulates microtubule dynamics under certain conditions. PMID:23798680

Asthana, Jayant; Kapoor, Sonia; Mohan, Renu; Panda, Dulal

2013-08-01

331

Modeling the regulatory network of histone acetylation in Saccharomyces cerevisiae  

Microsoft Academic Search

Acetylation of histones plays an important role in regulating transcription. Histone acetylation is mediated partly by the recruitment of specific histone acetyltransferases (HATs) and deacetylases (HDACs) to genomic loci by transcription factors, resulting in modulation of gene expression. Although several specific interactions between transcription factors and HATs and HDACs have been elaborated in Saccharomyces cerevisiae, the full regulatory network remains

Hung Pham; Roberto Ferrari; Shawn J Cokus; Siavash K Kurdistani; Matteo Pellegrini

2007-01-01

332

Epigenetic regulation of E2F-1-dependent Bnip3 transcription and cell death by nuclear factor-?B and histone deacetylase-1.  

PubMed

A delicate balance exists between cell growth and cell death. In the context of the adult myocardium, inappropriate or inordinate cell loss through an apoptotic process may profoundly influence cardiac structure, function, or both given the limited and meager ability of the heart for repair after injury. Earlier work by the authors' laboratory identified a close relation between cell cycle factor E2F-1 and hypoxia-inducible factor Bnip3 as the key regulator of apoptosis and autophagy in ventricular myocytes. Epigenetic changes by histone-modifying proteins, namely, histone deacetylases (HDACs) influence cell survival by altering the activity of histone core proteins, transcription factors, or both. This report highlights the intricate nature between the cellular factors E2F-1 and nuclear factor-?B (NF-?B) and the epigenetic regulation of Bnip3 gene transcription by HDAC1 for cell survival of ventricular myocytes. PMID:21293853

Gang, Hongying; Dhingra, Rimpy; Wang, Yan; Mughal, Wajihah; Gordon, Joseph W; Kirshenbaum, Lorrie A

2011-03-01

333

Antimalarial and Antileishmanial Activities of Histone Deacetylase Inhibitors with Triazole-Linked Cap Group  

PubMed Central

Histone deacetylase inhibitors (HDACi) are endowed with plethora of biological functions including anti-proliferative, anti-inflammatory, anti-parasitic, and cognition-enhancing activities. Parsing the structure–activity relationship (SAR) for each disease condition is vital for long-term therapeutic applications of HDACi. We report in the present study specific cap group substitution patterns and spacer-group chain lengths that enhance the antimalarial and antileishmanial activity of aryltriazolylhydroxamates-based HDACi. We identified many compounds that are several folds selectively cytotoxic to the plasmodium parasites compared to standard HDACi. Also, a few of these compounds have antileishmanial activity that rivals that of miltefosine, the only currently available oral agent against visceral leishmaniasis. The anti-parasite properties of several of these compounds tracked well with their anti-HDAC activities. The results presented here provide further evidence on the suitability of HDAC inhibition as a viable therapeutic option to curb infections caused by apicomplexan protozoans and trypanosomatids. PMID:19914074

Patil, Vishal; Guerrant, William; Chen, Po C.; Gryder, Berkley; Benicewicz, Derek B.; Khan, Shabana I.; Tekwani, Babu L.; Oyelere, Adegboyega K.

2009-01-01

334

New histone deacetylase inhibitors improve cisplatin antitumor properties against thoracic cancer cells  

PubMed Central

Histone deacetylase inhibitors (HDACi) have shown promising antitumor effects on numerous cancer cells including malignant pleural mesothelioma (MPM) and lung adenocarcinoma (ADCA) cells. However, clinical trials using these compounds alone have shown limited efficacy against solid tumors. Therefore, new molecules are being developed and combinations with classical chemotherapeutic drugs are being tested. Here, we have evaluated on three MPM and three lung ADCA cell lines the antitumor potential of four new HDACi compounds, either alone or in combination with cisplatin. These effects were compared with those of vorinostat, an HDACi approved for cancer treatments. First, we characterized the HDAC mRNA expression profiles of tumor cells and showed an increase of the classI/classII HDAC ratio. We then treated cancer cells with these new HDACi and observed a cell-death induction and an increase of HDACi target genes and proteins expression. This was particularly evident for NODH compound (pan-HDACi) which had similar effects at nanomolar concentrations as micromolar concentrations of vorinostat. Interestingly, we observed that the HDACi/cisplatin combination strongly increased cell-death and limited resistance-phenotype emergence as compared with results obtained when the drugs were used alone. These results could be exploited to develop MPM and lung ADCA treatments combining chemotherapeutic approaches. PMID:24980825

Gueugnon, Fabien; Cartron, Pierre-François; Charrier, Cedric; Bertrand, Philippe; Fonteneau, Jean-François; Gregoire, Marc; Blanquart, Christophe

2014-01-01

335

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

336

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

337

Combined DNA Methyltransferase and Histone Deacetylase Inhibition in the Treatment of Myeloid Neoplasms  

Microsoft Academic Search

Optimal reexpression of most genes silenced through pro- moter methylation requires the sequential application of DNA methyltransferase inhibitors followed by histone deacetylase inhibitors in tumor cell cultures. Patients with myelodys- plastic syndrome or acute myeloid leukemia (AML) were treated with the methyltransferase inhibitor 5-azacitidine (aza-CR) followed by the histone deacetylase inhibitor sodium phenylbutyrate. Major responses associated with cytogenetic complete response

Steven D. Gore; Stephen Baylin; Elizabeth Sugar; Carole B. Miller; Michael Carducci; Michael Grever; Oliver Galm; Tianna Dauses; Judith E. Karp; Michelle A. Rudek; Ming Zhao; B. Douglas Smith; Jasper Manning; Anchalee Jiemjit; George Dover; Abbie Mays; James Zwiebel; Anthony Murgo; Li-Jun Weng; James G. Herman; Medizinische Klinik; Universitaetsklinikum Aachen; Hochschule Aachen

338

Ku70 acetylation mediates neuroblastoma cell death induced by histone deacetylase inhibitors  

Microsoft Academic Search

Histone deacetylase inhibitors (HDACIs) are therapeutic drugs that inhibit deacetylase activity, thereby increasing acetylation of many proteins, including histones. HDACIs have antineoplastic effects in preclinical and clinical trials and are being considered for cancers with unmet therapeutic need, including neuroblastoma (NB). Uncertainty of how HDACI-induced protein acetylation leads to cell death, however, makes it difficult to determine which tumors are

Chitra Subramanian; Anthony W. Opipari Jr.; Xin Bian; Valerie P. Castle; Roland P. S. Kwok

2005-01-01

339

miR-326-histone deacetylase-3 feedback loop regulates the invasion and tumorigenic and angiogenic response to anti-cancer drugs.  

PubMed

Histone modification is known to be associated with multidrug resistance phenotypes. Cancer cell lines that are resistant or have been made resistant to anti-cancer drugs showed lower expression levels of histone deacetylase-3 (HDAC3), among the histone deacetylase(s), than cancer cell lines that were sensitive to anti-cancer drugs. Celastrol and Taxol decreased the expression of HDAC3 in cancer cell lines sensitive to anti-cancer drugs. HDAC3 negatively regulated the invasion, migration, and anchorage-independent growth of cancer cells. HDAC3 conferred sensitivity to anti-cancer drugs in vitro and in vivo. TargetScan analysis predicted miR-326 as a negative regulator of HDAC3. ChIP assays and luciferase assays showed a negative feedback loop between HDAC3 and miR-326. miR-326 decreased the apoptotic effect of anti-cancer drugs, and the miR-326 inhibitor increased the apoptotic effect of anti-cancer drugs. miR-326 enhanced the invasion and migration potential of cancer cells. The miR-326 inhibitor negatively regulated the tumorigenic, metastatic, and angiogenic potential of anti-cancer drug-resistant cancer cells. HDAC3 showed a positive feedback loop with miRNAs such as miR-200b, miR-217, and miR-335. miR-200b, miR-217, and miR-335 negatively regulated the expression of miR-326 and the invasion and migration potential of cancer cells while enhancing the apoptotic effect of anti-cancer drugs. TargetScan analysis predicted miR-200b and miR-217 as negative regulators of cancer-associated gene, a cancer/testis antigen, which is known to regulate the response to anti-cancer drugs. HDAC3 and miR-326 acted upstream of the cancer-associated gene. Thus, we show that the miR-326-HDAC3 feedback loop can be employed as a target for the development of anti-cancer therapeutics. PMID:25138213

Kim, Youngmi; Kim, Hyuna; Park, Hyunmi; Park, Deokbum; Lee, Hansoo; Lee, Yun Sil; Choe, Jongseon; Kim, Young Myeong; Jeoung, Dooil

2014-10-01

340

Cloning, chromosomal characterization and mapping of the NAD-dependent histone deacetylases gene sirtuin 1.  

PubMed

Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, which belongs to the silent information regulator 2 (Sir2) family of sirtuin histone deacetylases (HDACs). The yeast Sir2 protein and its mammalian derivatives play a central role in epigenetic gene silencing, DNA repair and recombination, cell-cycle, microtubule organization, and in the regulation of aging. We have isolated and characterized the human Sirt1 genomic sequence, which spans a region of 33,660 bp and which has one single genomic locus. Determination of the exon-intron splice junctions established that SIRT1 is encoded by 9 exons ranging in size from 80 bp (exon 6) to 2,120 bp (exon 9). Characterization of the 5' flanking genomic region, which precedes the Sirt1 open reading frame, revealed a CCAAT-box and a number of NF-kappaB and GATA transcription factor binding sites in addition to a small 350 bp CpG island. The 4,107 bp human Sirt1 mRNA has an open reading frame of 2,244 bp and encodes a 747 aa protein with a predictive molecular weight of 81.7 kDa and an isoelectric point of 4.55. Fluorescence in situ hybridization analysis localized the human Sirt1 gene to chromosome 10q21.3. PMID:16328012

Voelter-Mahlknecht, Susanne; Mahlknecht, Ulrich

2006-01-01

341

Histone Deacetylase Inhibitors: The Epigenetic Therapeutics That Repress Hypoxia-Inducible Factors  

PubMed Central

Histone deacetylase inhibitors (HDACIs) have been actively explored as a new generation of chemotherapeutics for cancers, generally known as epigenetic therapeutics. Recent findings indicate that several types of HDACIs repress angiogenesis, a process essential for tumor metabolism and progression. Accumulating evidence supports that this repression is mediated by disrupting the function of hypoxia-inducible factors (HIF-1, HIF-2, and collectively, HIF), which are the master regulators of angiogenesis and cellular adaptation to hypoxia. Since HIF also regulate glucose metabolism, cell survival, microenvironment remodeling, and other alterations commonly required for tumor progression, they are considered as novel targets for cancer chemotherapy. Though the precise biochemical mechanism underlying the HDACI-triggered repression of HIF function remains unclear, potential cellular factors that may link the inhibition of deacetylase activity to the repression of HIF function have been proposed. Here we review published data that inhibitors of type I/II HDACs repress HIF function by either reducing functional HIF-1? levels, or repressing HIF-? transactivation activity. In addition, underlying mechanisms and potential proteins involved in the repression will be discussed. A thorough understanding of HDACI-induced repression of HIF function may facilitate the development of future therapies to either repress or promote angiogenesis for cancer or chronic ischemic disorders, respectively. PMID:21151670

Chen, Shuyang; Sang, Nianli

2011-01-01

342

Human Cytomegalovirus pUL97 Regulates the Viral Major Immediate Early Promoter by Phosphorylation-Mediated Disruption of Histone Deacetylase 1 Binding  

PubMed Central

Human cytomegalovirus (HCMV) is a common agent of congenital infection and causes severe disease in immunocompromised patients. Current approved therapies focus on inhibiting viral DNA replication. The HCMV kinase pUL97 contributes to multiple stages of viral infection including DNA replication, controlling the cell cycle, and virion maturation. Our studies demonstrate that pUL97 also functions by influencing immediate early (IE) gene expression during the initial stages of infection. Inhibition of kinase activity using the antiviral compound maribavir or deletion of the UL97 gene resulted in decreased expression of viral immediate early genes during infection. Expression of pUL97 was sufficient to transactivate IE1 gene expression from the viral genome, which was dependent on viral kinase activity. We observed that pUL97 associates with histone deacetylase 1 (HDAC1). HDAC1 is a transcriptional corepressor that acts to silence expression of viral genes. We observed that inhibition or deletion of pUL97 kinase resulted in increased HDAC1 and decreased histone H3 lysine 9 acetylation associating with the viral major immediate early (MIE) promoter. IE expression during pUL97 inhibition or deletion was rescued following inhibition of deacetylase activity. HDAC1 associates with chromatin by protein-protein interactions. Expression of active but not inactive pUL97 kinase decreased HDAC1 interaction with the transcriptional repressor protein DAXX. Finally, using mass spectrometry, we found that HDAC1 is uniquely phosphorylated upon expression of pUL97. Our results support the conclusion that HCMV pUL97 kinase regulates viral immediate early gene expression by phosphorylation-mediated disruption of HDAC1 binding to the MIE promoter. PMID:23616659

Bigley, Tarin M.; Reitsma, Justin M.; Mirza, Shama P.

2013-01-01

343

Structure of HDAC3 bound to co-repressor and inositol tetraphosphate  

Microsoft Academic Search

Histone deacetylase enzymes (HDACs) are emerging cancer drug targets. They regulate gene expression by removing acetyl groups from lysine residues in histone tails, resulting in chromatin condensation. The enzymatic activity of most class I HDACs requires recruitment into multi-subunit co-repressor complexes, which are in turn recruited to chromatin by repressive transcription factors. Here we report the structure of a complex

Peter J. Watson; Louise Fairall; Guilherme M. Santos; John W. R. Schwabe

2012-01-01

344

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

345

Preclinical Studies in the mdx Mouse Model of Duchenne Muscular Dystrophy with the Histone Deacetylase Inhibitor Givinostat  

PubMed Central

Previous work has established the existence of dystrophin–nitric oxide (NO) signaling to histone deacetylases (HDACs) that is deregulated in dystrophic muscles. As such, pharmacological interventions that target HDACs (that is, HDAC inhibitors) are of potential therapeutic interest for the treatment of muscular dystrophies. In this study, we explored the effectiveness of long-term treatment with different doses of the HDAC inhibitor givinostat in mdx mice—the mouse model of Duchenne muscular dystrophy (DMD). This study identified an efficacy for recovering functional and histological parameters within a window between 5 and 10 mg/kg/d of givinostat, with evident reduction of the beneficial effects with 1 mg/kg/d dosage. The long-term (3.5 months) exposure of 1.5-month-old mdx mice to optimal concentrations of givinostat promoted the formation of muscles with increased cross-sectional area and reduced fibrotic scars and fatty infiltration, leading to an overall improvement of endurance performance in treadmill tests and increased membrane stability. Interestingly, a reduced inflammatory infiltrate was observed in muscles of mdx mice exposed to 5 and 10 mg/kg/d of givinostat. A parallel pharmacokinetic/pharmacodynamic analysis confirmed the relationship between the effective doses of givinostat and the drug distribution in muscles and blood of treated mice. These findings provide the preclinical basis for an immediate translation of givinostat into clinical studies with DMD patients. PMID:23552722

Consalvi, Silvia; Mozzetta, Chiara; Bettica, Paolo; Germani, Massimiliano; Fiorentini, Francesco; Del Bene, Francesca; Rocchetti, Maurizio; Leoni, Flavio; Monzani, Valmen; Mascagni, Paolo; Puri, Pier Lorenzo; Saccone, Valentina

2013-01-01

346

Histone Deacetylase Inhibitor, Trichostatin A, Improves Learning and Memory in High-Fat Diet-Induced Cognitive Deficits in Mice.  

PubMed

Metabolic syndrome is increasingly recognized for its effects on cognitive health. Recent studies have highlighted the role of histone deacetylases (HDACs) in metabolic syndrome and cognitive functions. The present study was designed to investigate the possible therapeutic role of a HDAC inhibitor, trichostatin A (TSA), in cognitive impairment associated with metabolic syndrome. To ascertain the mechanisms involved, we fed mice with high-fat diet (HFD) for 4 weeks and examined changes in behavioral and biochemical/oxidative stress markers. Mice subjected to HFD exhibited characteristic features of metabolic disorder, viz., hyperglycemia, hypertriglyceridemia, hypercholesterolemia, and lower high-density lipoprotein (HDL) cholesterol levels. Moreover, these mice showed severe deficits in learning and memory as assessed by the Morris water maze and passive avoidance tasks along with elevated oxidative stress and inflammatory markers in brain homogenates. The observed changes occurred concurrently with reduced brain-derived neurotrophic factor (BDNF). In contrast, the mice treated with the HDAC inhibitor, TSA (0.5 and 1 mg/kg, i.p.), showed a significant and dose-dependent reduction in serum glucose, triglycerides, and total cholesterol along with improvement in HDL-cholesterol levels and learning and memory performance. TSA treatment also results in alleviation of oxidative stress and neuroinflammatory markers. Moreover, TSA significantly augmented the BDNF levels in HFD-fed mice. Thus, based upon these observations, it may be suggested that HDAC inhibition could be a novel therapeutic strategy to combat cognitive impairment associated with metabolic syndrome. PMID:25391764

Sharma, Sorabh; Taliyan, Rajeev; Ramagiri, Shruti

2014-11-14

347

Class-specific histone/protein deacetylase inhibition protects against renal ischemia reperfusion injury and fibrosis formation.  

PubMed

Renal ischemia-reperfusion injury (IRI) is a common cause of renal dysfunction and renal failure. Histone/protein deacetylases (HDACs) regulate gene accessibility and higher order protein structures and may alter cellular responses to a variety of stresses. We investigated whether use of pan- and class-specific HDAC inhibitors (HDACi) could improve IRI tolerance in the kidney. Using a model of unilateral renal IRI, we investigated early renal function after IRI, and calculated fibrosis after IRI using an automated scoring system. We found that pan-HDAC inhibition using trichostatin (TSA) yielded significant renal functional benefit at 24-96?hours (p?HDAC inhibition with MS-275 yielded similar effects. Protection from fibrosis formation was also noted in a cold ischemia transplant model (p?

Levine, M H; Wang, Z; Bhatti, T R; Wang, Y; Aufhauser, D D; McNeal, S; Liu, Y; Cheraghlou, S; Han, R; Wang, L; Hancock, W W

2015-04-01

348

Human papillomavirus E7 enhances hypoxia-inducible factor 1-mediated transcription by inhibiting binding of histone deacetylases.  

PubMed

Infection by human papillomaviruses (HPV) leads to the formation of benign lesions, warts, and in some cases, cervical cancer. The formation of these lesions is dependent upon increased expression of proangiogenic factors. Angiogenesis is linked to tissue hypoxia through the activity of the oxygen-sensitive hypoxia-inducible factor 1? (HIF-1?). Our studies indicate that the HPV E7 protein enhances HIF-1 transcriptional activity whereas E6 functions to counteract the repressive effects of p53. Both high- and low-risk HPV E7 proteins were found to bind to HIF-1? through a domain located in the N-terminus. Importantly, the ability of E7 to enhance HIF-1 activity mapped to the C-terminus and correlated with the displacement of the histone deacetylases HDAC1, HDAC4, and HDAC7 from HIF-1? by E7. Our findings describe a novel role of the E7 oncoprotein in activating the function of a key transcription factor mediating hypoxic responses by blocking the binding of HDACs. PMID:21148070

Bodily, Jason M; Mehta, Kavi P M; Laimins, Laimonis A

2011-02-01

349

Histone deacetylase is required for the activation of Wnt/?-catenin signaling crucial for heart valve formation in zebrafish embryos.  

PubMed

During vertebrate heart valve formation, Wnt/?-catenin signaling induces BMP signals in atrioventricular canal (AVC) myocardial cells and underlying AVC endocardial cells then undergo endothelial-mesenchymal transdifferentiation (EMT) by receiving this BMP signals. Histone deacetylases (HDACs) have been implicated in numerous developmental processes by regulating gene expression. However, their specific roles in controlling heart valve development are largely unexplored. To investigate the role of HDACs in vertebrate heart valve formation, we treated zebrafish embryos with trichostatin A (TSA), an inhibitor of class I and II HDACs, from 36 to 48 h post-fertilization (hpf) during which heart looping and valve formation occur. Following TSA treatment, abnormal linear heart tube development was observed. In these embryos, expression of AVC myocardial bmp4 and AVC endocardial notch1b genes was markedly reduced with subsequent failure of EMT in the AVC endocardial cells. However, LiCl-mediated activation of Wnt/?-catenin signaling was able to rescue defective heart tube formation, bmp4 and notch1b expression, and EMT in the AVC region. Taken together, our results demonstrated that HDAC activity plays a pivotal role in vertebrate heart tube formation by activating Wnt/?-catenin signaling which induces bmp4 expression in AVC myocardial cells. PMID:22634317

Kim, Young-Seop; Kim, Myoung-Jin; Koo, Tae-Hee; Kim, Jun-Dae; Koun, Soonil; Ham, Hyung Jin; Lee, You Mie; Rhee, Myungchull; Yeo, Sang-Yeob; Huh, Tae-Lin

2012-06-22

350

Modifying histones to tame cancer: clinical development of sodium phenylbutyrate and other histone deacetylase inhibitors.  

PubMed

Compounds that inhibit histone deacetylase may enable the re-expression of silenced regulatory genes in neoplastic cells, reversing the malignant phenotype. Although several molecules that inhibit histone deacetylase are undergoing preclinical development, butyric acid derivatives have undergone clinical investigation for several years, initially for non-malignant indications and more recently for the treatment of cancer. Of the butyric acid derivatives, sodium phenylbutyrate has undergone the most extensive systematic investigation. Administration of phenylbutyrate by iv. and oral routes is well-tolerated clinically at concentrations which effect acetylation of histones in vitro. Higher doses lead to reversible CNS depression. The studies presented to date have been Phase I studies and do not enable assessment of efficacy. However, current development of phenylbutyrate is proceeding in combination with other agents based on rational biologically-based in vitro studies. The parallel development of combination therapy including phenylbutyrate and early clinical development of other, more potent histone deacetylase inhibitors will hopefully lead to feasible, clinically tolerable strategies for altering the malignant phenotype of cancer cells. PMID:11093362

Gore, S D; Carducci, M A

2000-12-01

351

Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes  

Microsoft Academic Search

The development of selective histone deacetylase (HDAC) inhibitors with anti-cancer and anti-inflammatory properties remains challenging in large part owing to the difficulty of probing the interaction of small molecules with megadalton protein complexes. A combination of affinity capture and quantitative mass spectrometry revealed the selectivity with which 16 HDAC inhibitors target multiple HDAC complexes scaffolded by ELM-SANT domain subunits, including

Carsten Hopf; Mikhail M Savitski; Antje Dittmann; Paola Grandi; Anne-Marie Michon; Judith Schlegl; Yann Abraham; Isabelle Becher; Giovanna Bergamini; Markus Boesche; Manja Delling; Birgit Dümpelfeld; Dirk Eberhard; Carola Huthmacher; Toby Mathieson; Daniel Poeckel; Valérie Reader; Katja Strunk; Gavain Sweetman; Ulrich Kruse; Gitte Neubauer; Nigel G Ramsden; Marcus Bantscheff; Gerard Drewes

2011-01-01

352

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

353

Benzyl isothiocyanate-mediated inhibition of histone deacetylase leads to NF-kappaB turnoff in human pancreatic carcinoma cells.  

PubMed

NF-kappaB/p65 is constitutively activated in pancreatic cancers, where it plays a critical role in the transcriptional activation of multiple cell survival genes. We have previously shown the apoptosis-inducing effects of benzyl isothiocyanate (BITC) in pancreatic cancer cells. We hypothesized that inhibition of NF-kappaB/p65 could be the mechanism of BITC-induced apoptosis. Therefore, the effect of BITC on NF-kappaB/p65 was evaluated in BxPC-3, Capan-2, and normal HPDE-6 cells by Western blotting, transcriptional and DNA-binding activity, and immunohistochemistry in the xenografted tumors. Our results reveal a remarkable decrease in the phosphorylation of NF-kappaB/p65 at Ser(536) in both BxPC-3 and Capan-2 cells by BITC treatment. The expression of NF-kappaB/p65 was downregulated significantly in BxPC-3 cells, whereas it remained unchanged in Capan-2 cells. BITC treatment caused a significant decrease in NF-kappaB transcriptional and DNA-binding activity in both BxPC-3 and Capan-2 cells. A drastic decrease was observed in the expression and reporter activity of cyclin D1 in both the cell lines. Moreover, BITC also caused a significant decrease in the expression and activity of histone deacetylase (HDAC) 1 and HDAC3 in BxPC-3 and HDAC3 in Capan-2 cells. Overexpression of HDAC1 or HDAC3 abrogated the effects of BITC. BITC treatment did not cause any change in HDAC expression in normal HPDE-6 cells. Immunohistochemical analysis of tumors from BITC-treated mice showed significantly reduced staining for NF-kappaB, cyclin D1, HDAC1, and HDAC3 compared with control. Our results suggest inhibition of HDAC1/HDAC3 by BITC as a plausible mechanism of NF-kappaB inactivation, resulting in the in vitro and in vivo growth suppression of pancreatic cancer cells. PMID:20484017

Batra, Sanjay; Sahu, Ravi P; Kandala, Prabodh K; Srivastava, Sanjay K

2010-06-01

354

Histone deacetylase inhibitors: can we consider potent anti-neoplastic agents for the treatment of asthma?  

PubMed

Histone deacetylase inhibitors have emerged as a new class of anti-cancer therapeutics due to their potent anti-proliferative and apoptotic effects in malignant cells. Accumulating evidence is indicating that histone deacetylase inhibitors may also have potential clinical utility in non-oncological applications, including asthma. However, the potential of histone deacetylase inhibitors in asthma remains controversial. For example, the mechanisms of action of the broad-spectrum histone deacetylase inhibitor, Trichostatin A, in animal models of allergic airways disease are conflicting. Further, there is evidence suggesting potential problems associated with histone deacetylase 2 inhibition and conventional glucocorticosteroid therapy. Similarly, disparate findings are emerging following modulation of the class III, sirtuin 1 enzyme. Indeed, it is becoming apparent that the mechanism of action may not be related to histone deacetylase inhibition activity per se. Further, there is only limited evidence that these compounds possess anti-inflammatory effects in models of asthma. In this review, we provide an overview of the biology of the metal-dependent and sirtuin deacetylases in the context of asthma. The controversies surrounding the potential use of histone deacetylase inhibitors in asthma are discussed and future directions involving the investigation of more specific analogues are explored. PMID:22964624

Royce, Simon G; Ververis, Katherine; Karagiannis, Tom C

2012-01-01

355

Histone deacetylase activity is necessary for left-right patterning during vertebrate development  

PubMed Central

Background Consistent asymmetry of the left-right (LR) axis is a crucial aspect of vertebrate embryogenesis. Asymmetric gene expression of the TGF? superfamily member Nodal related 1 (Nr1) in the left lateral mesoderm plate is a highly conserved step regulating the situs of the heart and viscera. In Xenopus, movement of maternal serotonin (5HT) through gap-junctional paths at cleavage stages dictates asymmetry upstream of Nr1. However, the mechanisms linking earlier biophysical asymmetries with this transcriptional control point are not known. Results To understand how an early physiological gradient is transduced into a late, stable pattern of Nr1 expression we investigated epigenetic regulation during LR patterning. Embryos injected with mRNA encoding a dominant-negative of Histone Deacetylase (HDAC) lacked Nr1 expression and exhibited randomized sidedness of the heart and viscera (heterotaxia) at stage 45. Timing analysis using pharmacological blockade of HDACs implicated cleavage stages as the active period. Inhibition during these early stages was correlated with an absence of Nr1 expression at stage 21, high levels of heterotaxia at stage 45, and the deposition of the epigenetic marker H3K4me2 on the Nr1 gene. To link the epigenetic machinery to the 5HT signaling pathway, we performed a high-throughput proteomic screen for novel cytoplasmic 5HT partners associated with the epigenetic machinery. The data identified the known HDAC partner protein Mad3 as a 5HT-binding regulator. While Mad3 overexpression led to an absence of Nr1 transcription and randomized the LR axis, a mutant form of Mad3 lacking 5HT binding sites was not able to induce heterotaxia, showing that Mad3's biological activity is dependent on 5HT binding. Conclusion HDAC activity is a new LR determinant controlling the epigenetic state of Nr1 from early developmental stages. The HDAC binding partner Mad3 may be a new serotonin-dependent regulator of asymmetry linking early physiological asymmetries to stable changes in gene expression during organogenesis. PMID:21599922

2011-01-01

356

Involvement of HDAC1 and HDAC3 in the Pathology of Polyglutamine Disorders: Therapeutic Implications for Selective HDAC1/HDAC3 Inhibitors  

PubMed Central

Histone deacetylases (HDACs) enzymes, which affect the acetylation status of histones and other important cellular proteins, have been recognized as potentially useful therapeutic targets for a broad range of human disorders. Emerging studies have demonstrated that different types of HDAC inhibitors show beneficial effects in various experimental models of neurological disorders. HDAC enzymes comprise a large family of proteins, with18 HDAC enzymes currently identified in humans. Hence, an important question for HDAC inhibitor therapeutics is which HDAC enzyme(s) is/are important for the amelioration of disease phenotypes, as it has become clear that individual HDAC enzymes play different biological roles in the brain. This review will discuss evidence supporting the involvement of HDAC1 and HDAC3 in polyglutamine disorders, including Huntington’s disease, and the use of HDAC1- and HDAC3-selective HDAC inhibitors as therapeutic intervention for these disorders. Further, while HDAC inhibitors are known alter chromatin structure resulting in changes in gene transcription, understanding the exact mechanisms responsible for the preclinical efficacy of these compounds remains a challenge. The potential chromatin-related and non-chromatin-related mechanisms of action of selective HDAC inhibitors will also be discussed. PMID:24865773

Thomas, Elizabeth A.

2014-01-01

357

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

358

Histone Deacetylases Regulate Gonadotropin-Releasing Hormone I Gene Expression via Modulating Otx2-Driven Transcriptional Activity  

PubMed Central

Background Precise coordination of the hypothalamic-pituitary-gonadal axis orchestrates the normal reproductive function. As a central regulator, the appropriate synthesis and secretion of gonadotropin-releasing hormone I (GnRH-I) from the hypothalamus is essential for the coordination. Recently, emerging evidence indicates that histone deacetylases (HDACs) play an important role in maintaining normal reproductive function. In this study, we identify the potential effects of HDACs on Gnrh1 gene transcription. Methodology/Principal Findings Inhibition of HDACs activities by trichostatin A (TSA) and valproic acid (VPA) promptly and dramatically repressed transcription of Gnrh1 gene in the mouse immortalized mature GnRH neuronal cells GT1–7. The suppression was connected with a specific region of Gnrh1 gene promoter, which contains two consensus Otx2 binding sites. Otx2 has been known to activate the basal and also enhancer-driven transcription of Gnrh1 gene. The transcriptional activity of Otx2 is negatively modulated by Grg4, a member of the Groucho-related-gene (Grg) family. In the present study, the expression of Otx2 was downregulated by TSA and VPA in GT1–7 cells, accompanied with the opposite changes of Grg4 expression. Chromatin immunoprecipitation and electrophoretic mobility shift assays demonstrated that the DNA-binding activity of Otx2 to Gnrh1 gene was suppressed by TSA and VPA. Overexpression of Otx2 partly abolished the TSA- and VPA-induced downregulation of Gnrh1 gene expression. Conclusions/Significance Our data indicate that HDAC inhibitors downregulate Gnrh1 gene expression via repressing Otx2-driven transcriptional activity. This study should provide an insight for our understanding on the effects of HDACs in the reproductive system and suggests that HDACs could be potential novel targets for the therapy of GnRH-related diseases. PMID:22761896

Ge, Yan; Xiao, Yun-Fei; Sun, Chang-Yan; Deng, Lin; Zhang, Wei; Wu, Si-Si; Liu, Ying; Jiang, Wei; Xin, Hong-Bo

2012-01-01

359

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

360

Divergent roles of HDAC1 and HDAC2 in the regulation of epidermal development and tumorigenesis  

PubMed Central

The histone deacetylases HDAC1 and HDAC2 remove acetyl moieties from lysine residues of histones and other proteins and are important regulators of gene expression. By deleting different combinations of Hdac1 and Hdac2 alleles in the epidermis, we reveal a dosage-dependent effect of HDAC1/HDAC2 activity on epidermal proliferation and differentiation. Conditional ablation of either HDAC1 or HDAC2 in the epidermis leads to no obvious phenotype due to compensation by the upregulated paralogue. Strikingly, deletion of a single Hdac2 allele in HDAC1 knockout mice results in severe epidermal defects, including alopecia, hyperkeratosis, hyperproliferation and spontaneous tumour formation. These mice display impaired Sin3A co-repressor complex function, increased levels of c-Myc protein, p53 expression and apoptosis in hair follicles (HFs) and misregulation of HF bulge stem cells. Surprisingly, ablation of HDAC1 but not HDAC2 in a skin tumour model leads to accelerated tumour development. Our data reveal a crucial function of HDAC1/HDAC2 in the control of lineage specificity and a novel role of HDAC1 as a tumour suppressor in the epidermis. PMID:24240174

Winter, Mircea; Moser, Mirjam A; Meunier, Dominique; Fischer, Carina; Machat, Georg; Mattes, Katharina; Lichtenberger, Beate M; Brunmeir, Reinhard; Weissmann, Simon; Murko, Christina; Humer, Christina; Meischel, Tina; Brosch, Gerald; Matthias, Patrick; Sibilia, Maria; Seiser, Christian

2013-01-01

361

Functional analysis of a RPD3 histone deacetylase homologue in Arabidopsis thaliana  

Microsoft Academic Search

Histone acetylation is modulated through the action of histone acetyltransferase and deacetylase, which play key roles in the regulation of eukaryotic gene expression. We have screened the expressed sequence tag database with the yeast histone deacetylase RPD3 sequence and identified two Arabidopsis homologues, AtRPD3A and AtRPD3B. The deduced amino acid sequences of AtRPD3A and AtRPD3B show high overall homology (55%

Keqiang Wu; Kamal Malik; Lining Tian; Daniel Brown; Brian Miki

2000-01-01

362

Histone Deacetylase Inhibition Activates Transgene Expression from Integration-Defective Lentiviral Vectors in Dividing and Non-Dividing Cells  

PubMed Central

Abstract Integration-defective lentiviral vectors (IDLVs) are being increasingly deployed in both basic and preclinical gene transfer settings. Often, however, the IDLV transgene expression profile is muted when compared to that of their integration-proficient counterparts. We hypothesized that the episomal nature of IDLVs turns them into preferential targets for epigenetic silencing involving chromatin-remodeling histone deacetylation. Therefore, vectors carrying an array of cis-acting elements and transcriptional unit components were assembled with the aid of packaging constructs encoding either the wild-type or the class I mutant D116N integrase moieties. The transduction levels and transgene-product yields provided by each vector class were assessed in the presence and absence of the histone deacetylase (HDAC) inhibitors sodium butyrate and trichostatin A. To investigate the role of the target cell replication status, we performed experiments in growth-arrested human mesenchymal stem cells and in post-mitotic syncytial myotubes. We found that IDLVs are acutely affected by HDACs regardless of their genetic makeup or target cell replication rate. Interestingly, the magnitude of IDLV transgene expression rescue due to HDAC inhibition varied in a vector backbone– and cell type–dependent manner. Finally, investigation of histone modifications by chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR) revealed a paucity of euchromatin marks distributed along IDLV genomes when compared to those measured on isogenic integration-competent vector templates. These findings support the view that IDLVs constitute preferential targets for epigenetic silencing involving histone deacetylation, which contributes to dampening their full transcriptional potential. Our data provide leads on how to most optimally titrate and deploy these promising episomal gene delivery vehicles. PMID:23140481

Pelascini, Laetitia P.L.; Janssen, Josephine M.

2013-01-01

363

Histone deacetylase inhibition activates transgene expression from integration-defective lentiviral vectors in dividing and non-dividing cells.  

PubMed

Integration-defective lentiviral vectors (IDLVs) are being increasingly deployed in both basic and preclinical gene transfer settings. Often, however, the IDLV transgene expression profile is muted when compared to that of their integration-proficient counterparts. We hypothesized that the episomal nature of IDLVs turns them into preferential targets for epigenetic silencing involving chromatin-remodeling histone deacetylation. Therefore, vectors carrying an array of cis-acting elements and transcriptional unit components were assembled with the aid of packaging constructs encoding either the wild-type or the class I mutant D116N integrase moieties. The transduction levels and transgene-product yields provided by each vector class were assessed in the presence and absence of the histone deacetylase (HDAC) inhibitors sodium butyrate and trichostatin A. To investigate the role of the target cell replication status, we performed experiments in growth-arrested human mesenchymal stem cells and in post-mitotic syncytial myotubes. We found that IDLVs are acutely affected by HDACs regardless of their genetic makeup or target cell replication rate. Interestingly, the magnitude of IDLV transgene expression rescue due to HDAC inhibition varied in a vector backbone- and cell type-dependent manner. Finally, investigation of histone modifications by chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR) revealed a paucity of euchromatin marks distributed along IDLV genomes when compared to those measured on isogenic integration-competent vector templates. These findings support the view that IDLVs constitute preferential targets for epigenetic silencing involving histone deacetylation, which contributes to dampening their full transcriptional potential. Our data provide leads on how to most optimally titrate and deploy these promising episomal gene delivery vehicles. PMID:23140481

Pelascini, Laetitia P L; Janssen, Josephine M; Gonçalves, Manuel A F V

2013-01-01

364

Histone deacetylase inhibitors valproic acid and sodium butyrate enhance prostaglandins release in lipopolysaccharide-activated primary microglia.  

PubMed

Modifications of histone deacetylases (HDACs) may be involved in microglia-driven neuroinflammatory responses. Recent studies suggest that several inflammatory molecules can regulate the extent of neurodegeneration and regeneration in the central nervous system (CNS). In the present study, we investigated the effects of HDAC inhibitors (HDACi) valproic acid (VPA) and sodium butyrate (NaBut) on the release of prostaglandins (PGs) in lipopolysaccharide (LPS)-activated microglia. We found that VPA and NaBut significantly enhanced LPS-induced release of PGE2, PGD2 and 8-iso-PGF2?. In addition, both compounds increased cyclooxygenase-2 and microsomal prostaglandin E synthase immunoreactivity and gene expression in LPS-stimulated microglia. Interestingly, treatment of activated microglia with HDACi also enhanced the gene expression and the release of different pro-inflammatory cytokines. Microglia activation with LPS leads to I?B-? degradation, as well as p38, ERK1/2 and JNK MAPKs phosphorylation and thus activation, which is not affected by treatment with VPA and NaBut. Furthermore, VPA and NaBut treatment induced histone acetylation at H3-K18 in microglia. We suggest that VPA and NaBut-driven increase in PGs release in LPS-activated microglia might be regulated at the transcriptional level and involves histone hyperacetylation. Our data demonstrate that VPA and NaBut are able to modulate microglia responses to inflammatory insults and thus possibly can regulate the CNS degenerative and regenerative processes. PMID:24480366

Singh, V; Bhatia, H S; Kumar, A; de Oliveira, A C P; Fiebich, B L

2014-04-18

365

Immunomodulatory effects of deacetylase inhibitors: therapeutic targeting of FOXP3+ regulatory T cells  

Microsoft Academic Search

Classical zinc-dependent histone deacetylases (HDACs) catalyse the removal of acetyl groups from histone tails and also from many non-histone proteins, including the transcription factor FOXP3, a key regulator of the development and function of regulatory T cells. Many HDAC inhibitors are in cancer clinical trials, but a subset of HDAC inhibitors has important anti-inflammatory or immunosuppressive effects that might be

Liqing Wang; Edwin F. de Zoeten; Mark I. Greene; Wayne W. Hancock

2009-01-01

366

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

367

HDAC signaling in neuronal development and axon regeneration.  

PubMed

The development and repair of the nervous system requires the coordinated expression of a large number of specific genes. Epigenetic modifications of histones represent an essential principle by which neurons regulate transcriptional responses and adapt to environmental cues. The post-translational modification of histones by chromatin-modifying enzymes histone acetyltransferases (HATs) and histone deacetylases (HDACs) shapes chromatin to adjust transcriptional profiles during neuronal development. Recent observations also point to a critical role for histone acetylation and deacetylation in the response of neurons to injury. While HDACs are mostly known to attenuate transcription through their deacetylase activity and their interaction with co-repressors, these enzymes are also found in the cytoplasm where they display transcription-independent activities by regulating the function of diverse proteins. Here we discuss recent studies that go beyond the traditional use of HDAC inhibitors and have begun to dissect the roles of individual HDAC isoforms in neuronal development and repair after injury. PMID:24727244

Cho, Yongcheol; Cavalli, Valeria

2014-08-01

368

Class IIa Histone Deacetylases and Myocyte Enhancer Factor 2 Proteins Regulate the Mesenchymal-to-Epithelial Transition of Somatic Cell Reprogramming*  

PubMed Central

Class IIa histone deacetylases (HDACs) and myocyte enhancer factor 2 (MEF2) proteins compose a signaling module that orchestrates lineage specification during embryogenesis. We show here that this module also regulates the generation of mouse induced pluripotent stem cells by defined transcription factors. Class IIa HDACs and MEF2 proteins rise steadily during fibroblast reprogramming to induced pluripotent stem cells. MEF2 proteins tend to block the process by inducing the expression of Tgf? cytokines, which impairs the necessary phase of mesenchymal-to-epithelial transition (MET). Conversely, class IIa HDACs endeavor to suppress the activity of MEF2 proteins, thus enhancing the MET and colony formation efficiency. Our work highlights an unexpected role for a developmental axis in somatic cell reprogramming and provides new insight into how the MET is regulated in this context. PMID:23467414

Zhuang, Qiang; Qing, Xiaobing; Ying, Yue; Wu, Haitao; Benda, Christina; Lin, Jiao; Huang, Zhijian; Liu, Longqi; Xu, Yan; Bao, Xichen; Qin, Baoming; Pei, Duanqing; Esteban, Miguel A.

2013-01-01

369

Syntheses and discovery of a novel class of cinnamic hydroxamates as histone deacetylase inhibitors by multimodality molecular imaging in living subjects.  

PubMed

Histone deacetylases (HDAC) that regulate gene expression are being explored as cancer therapeutic targets. In this study, we focused on HDAC6 based on its ability to inhibit cancerous Hsp90 chaperone activities by disrupting Hsp90/p23 interactions. To identify novel HDAC6 inhibitors, we used a dual-luciferase reporter system in cell culture and living mice by bioluminescence imaging (BLI). On the basis of existing knowledge, a library of hydrazone compounds was generated for screening by coupling cinnamic hydroxamates with aldehydes and ketones. Potency and selectivity were determined by in vitro HDAC profiling assays, with further evaluation to inhibit Hsp90(?/?)/p23 interactions by BLI. In this manner, we identified compound 1A12 as a dose-dependent inhibitor of Hsp90(?/?)/p23 interactions, UKE-1 myeloid cell proliferation, p21(waf1) upregulation, and acetylated histone H3 levels. 1A12 was efficacious in tumor xenografts expressing Hsp90(?)/p23 reporters relative to carrier control-treated mice as determined by BLI. Small animal (18)F-FDG PET/CT imaging on the same cohort showed that 1A12 also inhibited glucose metabolism relative to control subjects. Ex vivo analyses of tumor lysates showed that 1A12 administration upregulated acetylated-H3 by approximately 3.5-fold. Taken together, our results describe the discovery and initial preclinical validation of a novel selective HDAC inhibitor. PMID:25320008

Chan, C T; Qi, J; Smith, W; Paranol, R; Mazitschek, R; West, N; Reeves, R; Chiosis, G; Schreiber, S L; Bradner, J E; Paulmurugan, R; Gambhir, S S

2014-12-15

370

The Histone Deacetylase Inhibitor Vorinostat (SAHA) Increases the Susceptibility of Uninfected CD4+ T Cells to HIV by Increasing the Kinetics and Efficiency of Postentry Viral Events  

PubMed Central

ABSTRACT Latently infected cells remain a primary barrier to eradication of HIV-1. Over the past decade, a better understanding of the molecular mechanisms by which latency is established and maintained has led to the discovery of a number of compounds that selectively reactivate latent proviruses without inducing polyclonal T cell activation. Recently, the histone deacetylase (HDAC) inhibitor vorinostat has been demonstrated to induce HIV transcription from latently infected cells when administered to patients. While vorinostat will be given in the context of antiretroviral therapy (ART), infection of new cells by induced virus remains a clinical concern. Here, we demonstrate that vorinostat significantly increases the susceptibility of CD4+ T cells to infection by HIV in a dose- and time-dependent manner that is independent of receptor and coreceptor usage. Vorinostat does not enhance viral fusion with cells but rather enhances the kinetics and efficiency of postentry viral events, including reverse transcription, nuclear import, and integration, and enhances viral production in a spreading-infection assay. Selective inhibition of the cytoplasmic class IIb HDAC6 with tubacin recapitulated the effect of vorinostat. These findings reveal a previously unknown cytoplasmic effect of HDAC inhibitors promoting productive infection of CD4+ T cells that is distinct from their well-characterized effects on nuclear histone acetylation and long-terminal-repeat (LTR) transcription. Our results indicate that careful monitoring of patients and ART intensification are warranted during vorinostat treatment and indicate that HDAC inhibitors that selectively target nuclear class I HDACs could reactivate latent HIV without increasing the susceptibility of uninfected cells to HIV. IMPORTANCE HDAC inhibitors, particularly vorinostat, are currently being investigated clinically as part of a “shock-and-kill” strategy to purge latent reservoirs of HIV. We demonstrate here that vorinostat increases the susceptibility of uninfected CD4+ T cells to infection with HIV, raising clinical concerns that vorinostat may reseed the viral reservoirs it is meant to purge, particularly under conditions of suboptimal drug exposure. We demonstrate that vorinostat acts following viral fusion and enhances the kinetics and efficiency of reverse transcription, nuclear import, and integration. The effect of vorinostat was recapitulated using the cytoplasmic histone deacetylase 6 (HDAC6) inhibitor tubacin, revealing a novel and previously unknown cytoplasmic mechanism of HDAC inhibitors on HIV replication that is distinct from their well-characterized effects of long-terminal-repeat (LTR)-driven gene expression. Moreover, our results suggest that treatment of patients with class I-specific HDAC inhibitors could induce latent viruses without increasing the susceptibility of uninfected cells to HIV. PMID:25008921

Lucera, Mark B.; Tilton, Carisa A.; Mao, Hongxia; Dobrowolski, Curtis; Tabler, Caroline O.; Haqqani, Aiman A.; Karn, Jonathan

2014-01-01

371

Perinuclear positioning of the inactive human cystic fibrosis gene depends on CTCF, A-type lamins and an active histone deacetylase.  

PubMed

The nuclear positioning of mammalian genes often correlates with their functional state. For instance, the human cystic fibrosis transmembrane conductance regulator (CFTR) gene associates with the nuclear periphery in its inactive state, but occupies interior positions when active. It is not understood how nuclear gene positioning is determined. Here, we investigated trichostatin A (TSA)-induced repositioning of CFTR in order to address molecular mechanisms controlling gene positioning. Treatment with the histone deacetylase (HDAC) inhibitor TSA induced increased histone acetylation and CFTR repositioning towards the interior within 20 ?min. When CFTR localized in the nuclear interior (either after TSA treatment or when the gene was active) consistent histone H3 hyperacetylation was observed at a CTCF site close to the CFTR promoter. Knockdown experiments revealed that CTCF was essential for perinuclear CFTR positioning and both, CTCF knockdown as well as TSA treatment had similar and CFTR-specific effects on radial positioning. Furthermore, knockdown experiments revealed that also A-type lamins were required for the perinuclear positioning of CFTR. Together, the results showed that CTCF, A-type lamins and an active HDAC were essential for perinuclear positioning of CFTR and these components acted on a CTCF site adjacent to the CFTR promoter. The results are consistent with the idea that CTCF bound close to the CFTR promoter, A-type lamins and an active HDAC form a complex at the nuclear periphery, which becomes disrupted upon inhibition of the HDAC, leading to the observed release of CFTR. PMID:22422629

Muck, Joscha S; Kandasamy, Karthikeyan; Englmann, Andreas; Günther, Martin; Zink, Daniele

2012-08-01

372

Coumarin-suberoylanilide hydroxamic acid as a fluorescent probe for determining binding affinities and off-rates of histone deacetylase inhibitors.  

PubMed

Histone deacetylases (HDACs) are intimately involved in epigenetic regulation and, thus, are one of the key therapeutic targets for cancer, and two HDAC inhibitors, namely suberoylanilide hydroxamic acid (SAHA) and romidepsin, have been recently approved for cancer treatment. Because the screening and detailed characterization of HDAC inhibitors has been time-consuming, we synthesized coumarin-SAHA (c-SAHA) as a fluorescent probe for determining the binding affinities (K(d)) and the dissociation off-rates (k(off)) of the enzyme-inhibitor complexes. The determination of the above parameters relies on the changes in the fluorescence emission intensity (?(ex)=325 nm, ?(em)=400 nm) of c-SAHA due to its competitive binding against other HDAC inhibitors, and such determination neither requires employment of polarization accessories nor is dependent on the fluorescence energy transfer from the enzyme's tryptophan residues to the probe. Our highly sensitive and robust analytical protocol presented here is applicable to most of the HDAC isozymes, and it can be easily adopted in a high-throughput mode for screening the HDAC inhibitors as well as for quantitatively determining their K(d) and k(off) values. PMID:20816742

Singh, Raushan K; Mandal, Tanmay; Balasubramanian, Narayanaganesh; Cook, Gregory; Srivastava, D K

2011-01-15

373

Arabidopsis thaliana histone deacetylase 1 (AtHD1) is localized in euchromatic regions and demonstrates histone deacetylase activity in vitro  

PubMed Central

Arabidopsis thaliana histone deacetylase 1 (AtHD1 or AtHDA19), a homolog of yeast RPD3, is a global regulator of many physiological and developmental processes in plants. In spite of the genetic evidence for a role of AtHD1 in plant gene regulation and development, the biochemical and cellular properties of AtHD1 are poorly understood. Here we report cellular localization patterns of AtHD1 in vivo and histone deacetylase activity in vitro. The transient and stable expression of a green fluorescent (GFP)-tagged AtHD1 in onion cells and in roots, seeds and leaves of the transgenic Arabidopsis, respectively, revealed that AtHD1 is localized in the nucleus presumably in the euchromatic regions and excluded from the nucleolus. The localization patterns of AtHD1 are different from those of AtHD2 and AtHDA6 that are involved in nucleolus formation and silencing of transgenes and repeated DNA elements, respectively. In addition, a histone deacetylase activity assay showed that the recombinant AtHD1 produced in bacteria demonstrated a specific histone deacetylase activity in vitro. The data suggest that AtHD1 is a nuclear protein and possesses histone deacetylase activities responsible for global transcriptional regulation important to plant growth and development. PMID:16699543

Fong, Paulus M; Tian, Lu; Chen, Z Jeffrey

2007-01-01

374

Phase II trial of the histone deacetylase inhibitor romidepsin in patients with recurrent/metastatic head and neck cancer  

PubMed Central

Objectives Patients with advanced squamous cell carcinoma of the head and neck (SCCHN) have limited treatment options. Inhibition of histone deacetylases (HDACs) represents a novel therapeutic approach warranting additional investigation in solid tumors. Methods A phase II trial of single agent romidepsin, an HDAC inhibitor, was performed in 14 patients with SCCHN who provided consent for pre- and post-therapy samples of accessible tumor, blood and uninvolved oral mucosa. Romidepsin was administered at 13 mg/m2 as a 4-hour intravenous infusion on days 1, 8 and 15 of 28 day cycles, with response assessment by RECIST every 8 weeks. Results Objective responses were not observed, although 2 heavily pretreated patients had brief clinical disease stabilization. Observed toxicities were expected, including frequent severe fatigue. Immunohistochemical analysis of 7 pre- and post-treatment tumor pairs demonstrated induction of p21Waf1/Cip1 characteristic of HDAC inhibition, as well as decreased Ki67 staining. Exploratory microarray analyses of mucosal and tumor samples detected changes in gene expression following romidepsin treatment that were most commonly associated with regulation of transcription, cell cycle control, signal transduction, and electron transport. Treatment with romidepsin did not alter the extent of DNA methylation of candidate gene loci (including CDH1 and hMLH1) in SCCHN tumors. Conclusions Single agent romidepsin has limited a