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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.

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

2003-01-01

2

A Role for Histone Deacetylase Activity in HDAC1-Mediated Transcriptional Repression  

Microsoft Academic Search

Treatment of mammalian cells with small molecule histone deacetylase (HDAC) inhibitors induces changes in the transcription of specific genes. These changes correlate directly with an increase in the acetylation levels of all four core histones in vivo. Antibodies directed against endogenous HDAC1, HDAC2, or HDAC3 immunoprecipitate histone deacetylase activity that is inhibited in vitro by the small molecule trapoxin (TPX),

Christian A. Hassig; Jeffrey K. Tong; Tracey C. Fleischer; Takashi Owa; Phyllis G. Grable; Donald E. Ayer; Stuart L. Schreiber

1998-01-01

3

Transcription Regulation by Class III Histone Deacetylases (HDACs)--Sirtuins  

PubMed Central

Sirtuins are NAD+-dependent histone deacetylases (Class III HDACs). Recently, Sirtuins have been shown to play important roles, both direct and indirect, in transcriptional regulation. This transcriptional control, through incorporation of Sirtuins into transcription complexes and deacetylation of histones locally at gene promoters, or direct interaction with specific transcription factors, is central to the participation of Sirtuins in multiple diverse processes, including aging, apoptosis, hormone responses, stress tolerance, differentiation, metabolism and development. Here we review the contribution of the Sirtuin family, at multiple molecular levels, to transcriptional regulation.

Dai, Yan; Faller, Douglas V.

2008-01-01

4

A role for histone deacetylase activity in HDAC1-mediated transcriptional repression.  

PubMed

Treatment of mammalian cells with small molecule histone deacetylase (HDAC) inhibitors induces changes in the transcription of specific genes. These changes correlate directly with an increase in the acetylation levels of all four core histones in vivo. Antibodies directed against endogenous HDAC1, HDAC2, or HDAC3 immunoprecipitate histone deacetylase activity that is inhibited in vitro by the small molecule trapoxin (TPX), and all three HDACs are retained by a TPX-affinity matrix. HDAC1 and HDAC2 are associated in HeLa cells in a complex that is predominantly separate from an HDAC3 immune complex. Both Jurkat HDAC1 and HeLa HDAC1/2 immune complexes deacetylate all four core histones and recombinant HDAC1 deacetylates free and nucleosomal histones in vitro. Purified recombinant HDAC1 deacetylates core histones in the absence of protein cofactors. Site-directed mutagenesis was used to identify residues required for the enzymatic and structural integrity of HDAC1. Mutation of any one of four conserved residues causes deleterious effects on deacetylase activity and a reduced ability to bind a TPX-affinity matrix. A subset of these mutations also cause a decreased interaction with the HDAC1-associated proteins RbAp48 and mSin3A. Disruption of histone deacetylase activity either by TPX or by direct mutation of a histidine presumed to be in the active site abrogates HDAC1-mediated transcriptional repression of a targeted reporter gene in vivo. PMID:9520398

Hassig, C A; Tong, J K; Fleischer, T C; Owa, T; Grable, P G; Ayer, D E; Schreiber, S L

1998-03-31

5

The histone deacetylase HDAC3 targets RbAp48 to the retinoblastoma protein  

Microsoft Academic Search

The product of the retinoblastoma susceptibility gene, the Rb protein, functions partly through tran- scriptional repression of E2F-regulated genes. Repression by Rb is mediated, at least in part, by a histone deacetylase complex, whose enzymatic activity relies on HDAC1, HDAC2 or HDAC3. Recently, we have shown that the Rb-associated histone deacetylase complex contains RbAp48 protein, which interacts with HDAC1 and

Estelle Nicolas; Slimane Ait-Si-Ali; Didier Trouche

2001-01-01

6

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

Microsoft Academic Search

Histone deacetylases (HDACs) are key transcription regulators that function by deacetylating histones\\/transcription factors and modifying chromatin structure. In this work, we showed that chemical inhibition of HDACs by valproic acid (VPA) led to impaired liver development in zebrafish mainly by inhibiting specification, budding, and differentiation. Formation of exocrine pancreas but not endocrine pancreas was also inhibited. The liver defects induced

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

2008-01-01

7

Specific Control of Pancreatic Endocrine ?- and ?-Cell Mass by Class IIa Histone Deacetylases HDAC4, HDAC5, and HDAC9  

PubMed Central

OBJECTIVE Class IIa histone deacetylases (HDACs) belong to a large family of enzymes involved in protein deacetylation and play a role in regulating gene expression and cell differentiation. Previously, we showed that HDAC inhibitors modify the timing and determination of pancreatic cell fate. The aim of this study was to determine the role of class IIa HDACs in pancreas development. RESEARCH DESIGN AND METHODS We took a genetic approach and analyzed the pancreatic phenotype of mice lacking HDAC4, -5, and -9. We also developed a novel method of lentiviral infection of pancreatic explants and performed gain-of-function experiments. RESULTS We show that class IIa HDAC4, -5, and -9 have an unexpected restricted expression in the endocrine ?- and ?-cells of the pancreas. Analyses of the pancreas of class IIa HDAC mutant mice revealed an increased pool of insulin-producing ?-cells in Hdac5?/? and Hdac9?/? mice and an increased pool of somatostatin-producing ?-cells in Hdac4?/? and Hdac5?/? mice. Conversely, HDAC4 and HDAC5 overexpression showed a decreased pool of insulin-producing ?-cells and somatostatin-producing ?-cells. Finally, treatment of pancreatic explants with the selective class IIa HDAC inhibitor MC1568 enhances expression of Pax4, a key factor required for proper ?-and ?-cell differentiation and amplifies endocrine ?- and ?-cells. CONCLUSIONS We conclude that HDAC4, -5, and -9 are key regulators to control the pancreatic ?/?-cell lineage. These results highlight the epigenetic mechanisms underlying the regulation of endocrine cell development and suggest new strategies for ?-cell differentiation-based therapies.

Lenoir, Olivia; Flosseau, Kathleen; Ma, Feng Xia; Blondeau, Bertrand; Mai, Antonello; Bassel-Duby, Rhonda; Ravassard, Philippe; Olson, Eric N.; Haumaitre, Cecile; Scharfmann, Raphael

2011-01-01

8

The Biology of HDAC8, a Unique Class I Histone Deacetylase  

Microsoft Academic Search

HDAC8 is a class I member of the histone deacetylases family, although lying phylogenetically close to the evolutionary boundary\\u000a between class I and class II HDACs. After a comprehensive review of the current understanding of the biology of HDAC8 and\\u000a its gene, we present recent evidenc indicating that this HDAC is selectively expressed by cells showing smooth muscle cell\\u000a differentiation,

David Waltregny; Vincent Castronovo

9

The histone deacetylase HDAC3 targets RbAp48 to the retinoblastoma protein.  

PubMed

The product of the retinoblastoma susceptibility gene, the Rb protein, functions partly through transcriptional repression of E2F-regulated genes. Repression by Rb is mediated, at least in part, by a histone deacetylase complex, whose enzymatic activity relies on HDAC1, HDAC2 or HDAC3. Recently, we have shown that the Rb-associated histone deacetylase complex contains RbAp48 protein, which interacts with HDAC1 and HDAC2. RbAp48 could favour the deacetylation of histones since it binds directly to histone H4. In agreement with that, we show that transcriptional repression of E2F activity requires the presence of RbAp48. HDAC3 was thought not to interact with RbAp48. However, we found that it shared with HDAC1 the ability to favour the recruitment of RbAp48 to Rb. This latter effect was unlikely to be due to activation of Rb function, since HDAC3 did not increase Rb-E2F1 interaction. Rather, we found, surprisingly, that HDAC3 could physically interact with RbAp48 both in vitro and in living cells. Taken together, our data suggest a model in which Rb mediates the recruitment to E2F-regulating promoters of a repressive complex containing either HDAC1, HDAC2 or HDAC3 and the histone-binding protein RbAp48. PMID:11470869

Nicolas, E; Ait-Si-Ali, S; Trouche, D

2001-08-01

10

Identification of HDAC10, a novel class II human histone deacetylase containing a leucine-rich domain  

Microsoft Academic Search

Histone acetylation is important for regulating chro- matin structure and gene expression. Three classes of mammalian histone deacetylases have been identified. Among class II, there are five known members, namely HDAC4, HDAC5, HDAC6, HDAC7 and HDAC9. Here we describe the identification and characteriza- tion of a novel class II member termed HDAC10. It is a 669 residue polypeptide with a

Jenny J. Tong; Jianhong Liu; Nicholas R. Bertos; Xiang-Jiao Yang

2002-01-01

11

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

PubMed

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

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

2008-05-01

12

Protein Kinase CK2 Regulates the Dimerization of Histone Deacetylase 1 (HDAC1) and HDAC2 during Mitosis*  

PubMed Central

Histone deacetylase 1 (HDAC1) and HDAC2 are components of corepressor complexes that are involved in chromatin remodeling and regulation of gene expression by regulating dynamic protein acetylation. HDAC1 and -2 form homo- and heterodimers, and their activity is dependent upon dimer formation. Phosphorylation of HDAC1 and/or HDAC2 in interphase cells is required for the formation of HDAC corepressor complexes. In this study, we show that during mitosis, HDAC2 and, to a lesser extent, HDAC1 phosphorylation levels dramatically increase. When HDAC1 and -2 are displaced from the chromosome during metaphase, they dissociate from each other, but each enzyme remains in association with components of the HDAC corepressor complexes Sin3, NuRD, and CoREST as homodimers. Enzyme inhibition studies and mutational analyses demonstrated that protein kinase CK2-catalyzed phosphorylation of HDAC1 and -2 is crucial for the dissociation of these two enzymes. These results suggest that corepressor complexes, including HDAC1 or HDAC2 homodimers, might target different cellular proteins during mitosis.

Khan, Dilshad H.; He, Shihua; Yu, Jenny; Winter, Stefan; Cao, Wenguang; Seiser, Christian; Davie, James R.

2013-01-01

13

Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease  

PubMed Central

The worldwide burden of sickle cell disease is enormous, with over 200,000 infants born with the disease each year in Africa alone. Induction of fetal hemoglobin is a validated strategy to improve symptoms and complications of this disease. The development of targeted therapies has been limited by the absence of discrete druggable targets. We developed a unique bead-based strategy for the identification of inducers of fetal hemoglobin transcripts in primary human erythroid cells. A small-molecule screen of bioactive compounds identified remarkable class-associated activity among histone deacetylase (HDAC) inhibitors. Using a chemical genetic strategy combining focused libraries of biased chemical probes and reverse genetics by RNA interference, we have identified HDAC1 and HDAC2 as molecular targets mediating fetal hemoglobin induction. Our findings suggest the potential of isoform-selective inhibitors of HDAC1 and HDAC2 for the treatment of sickle cell disease.

Bradner, James E.; Mak, Raymond; Tanguturi, Shyam K.; Mazitschek, Ralph; Haggarty, Stephen J.; Ross, Kenneth; Chang, Cindy Y.; Bosco, Jocelyn; West, Nathan; Morse, Elizabeth; Shen, John Paul; Kwiatkowski, Nicholas P.; Gheldof, Nele; Dekker, Job; DeAngelo, Daniel J.; Carr, Steven A.; Schreiber, Stuart L.; Golub, Todd R.; Ebert, Benjamin L.

2010-01-01

14

Histone deacetylases and cancer  

Microsoft Academic Search

Histone deacetylases (HDACs) regulate the expression and activity of numerous proteins involved in both cancer initiation and cancer progression. By removal of acetyl groups from histones, HDACs create a non-permissive chromatin conformation that prevents the transcription of genes that encode proteins involved in tumorigenesis. In addition to histones, HDACs bind to and deacetylate a variety of other protein targets including

M A Glozak; E Seto

2007-01-01

15

Histone Deacetylase 6 (HDAC6) Is an Essential Modifier of Glucocorticoid-Induced Hepatic Gluconeogenesis  

PubMed Central

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.

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

2012-01-01

16

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

17

Histone Deacetylase (HDAC) Activity Is Critical for Embryonic Kidney Gene Expression, Growth, and Differentiation*  

PubMed Central

Histone deacetylases (HDACs) regulate fundamental biological processes such as cellular proliferation, differentiation, and survival via genomic and nongenomic effects. This study examined the importance of HDAC activity in the regulation of gene expression and differentiation of the developing mouse kidney. Class I HDAC1–3 and class II HDAC4, -7, and -9 genes are developmentally regulated. Moreover, HDAC1–3 are highly expressed in nephron precursors. Short term treatment of cultured mouse embryonic kidneys with HDAC inhibitors (HDACi) induced global histone H3 and H4 hyperacetylation and H3K4 hypermethylation. However, genome-wide profiling revealed that the HDAC-regulated transcriptome is restricted and encompasses regulators of the cell cycle, Wnt/?-catenin, TGF-?/Smad, and PI3K-AKT pathways. Further analysis demonstrated that base-line expression of key developmental renal regulators, including Osr1, Eya1, Pax2/8, WT1, Gdnf, Wnt9b, Sfrp1/2, and Emx2, is dependent on intact HDAC activity. Treatment of cultured embryonic kidney cells with HDACi recapitulated these gene expression changes, and chromatin immunoprecipitation assays revealed that HDACi is associated with histone hyperacetylation of Pax2/Pax8, Gdnf, Sfrp1, and p21. Gene knockdown studies demonstrated that HDAC1 and HDAC2 play a redundant role in regulation of Pax2/8 and Sfrp1 but not Gdnf. Long term treatment of embryonic kidneys with HDACi impairs the ureteric bud branching morphogenesis program and provokes growth arrest and apoptosis. We conclude that HDAC activity is critical for normal embryonic kidney homeostasis, and we implicate class I HDACs in the regulation of early nephron gene expression, differentiation, and survival.

Chen, Shaowei; Bellew, Christine; Yao, Xiao; Stefkova, Jana; Dipp, Susana; Saifudeen, Zubaida; Bachvarov, Dimcho; El-Dahr, Samir S.

2011-01-01

18

Histone deacetylase (HDAC) activity is critical for embryonic kidney gene expression, growth, and differentiation.  

PubMed

Histone deacetylases (HDACs) regulate fundamental biological processes such as cellular proliferation, differentiation, and survival via genomic and nongenomic effects. This study examined the importance of HDAC activity in the regulation of gene expression and differentiation of the developing mouse kidney. Class I HDAC1-3 and class II HDAC4, -7, and -9 genes are developmentally regulated. Moreover, HDAC1-3 are highly expressed in nephron precursors. Short term treatment of cultured mouse embryonic kidneys with HDAC inhibitors (HDACi) induced global histone H3 and H4 hyperacetylation and H3K4 hypermethylation. However, genome-wide profiling revealed that the HDAC-regulated transcriptome is restricted and encompasses regulators of the cell cycle, Wnt/?-catenin, TGF-?/Smad, and PI3K-AKT pathways. Further analysis demonstrated that base-line expression of key developmental renal regulators, including Osr1, Eya1, Pax2/8, WT1, Gdnf, Wnt9b, Sfrp1/2, and Emx2, is dependent on intact HDAC activity. Treatment of cultured embryonic kidney cells with HDACi recapitulated these gene expression changes, and chromatin immunoprecipitation assays revealed that HDACi is associated with histone hyperacetylation of Pax2/Pax8, Gdnf, Sfrp1, and p21. Gene knockdown studies demonstrated that HDAC1 and HDAC2 play a redundant role in regulation of Pax2/8 and Sfrp1 but not Gdnf. Long term treatment of embryonic kidneys with HDACi impairs the ureteric bud branching morphogenesis program and provokes growth arrest and apoptosis. We conclude that HDAC activity is critical for normal embryonic kidney homeostasis, and we implicate class I HDACs in the regulation of early nephron gene expression, differentiation, and survival. PMID:21778236

Chen, Shaowei; Bellew, Christine; Yao, Xiao; Stefkova, Jana; Dipp, Susana; Saifudeen, Zubaida; Bachvarov, Dimcho; El-Dahr, Samir S

2011-09-16

19

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

20

Novel Histone Deacetylase Inhibitors.  

National Technical Information Service (NTIS)

HDAC (histone deacetylase) is a novel target for anti-cancer drug discovery. A database of guinoline compounds was characterized for the ability to inhibit HDAC, promote differentiation and cell death in tissue culture lines of human breast cancer. Antima...

J. S. Strobl

2003-01-01

21

The p65 (RelA) Subunit of NF B Interacts with the Histone Deacetylase (HDAC) Corepressors HDAC1 and HDAC2 To Negatively Regulate Gene Expression  

Microsoft Academic Search

Regulation of NF-B transactivation function is controlled at several levels, including interactions with coactivator proteins. Here we show that the transactivation function of NF-B is also regulated through interaction of the p65 (RelA) subunit with histone deacetylase (HDAC) corepressor proteins. Our results show that inhibition of HDAC activity with trichostatin A (TSA) results in an increase in both basal and

BRIAN P. ASHBURNER; SANDY D. WESTERHEIDE

2001-01-01

22

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

PubMed Central

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

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

2014-01-01

23

Histone deacetylase (HDAC) 10 suppresses cervical cancer metastasis through inhibition of matrix metalloproteinase (MMP) 2 and 9 expression.  

PubMed

Aberrant expression of histone deacetylases (HDACs) is associated with carcinogenesis. Some HDAC inhibitors are widely considered as promising anticancer therapeutics. A major obstacle for development of HDAC inhibitors as highly safe and effective anticancer therapeutics is that our current knowledge on the contributions of different HDACs in various cancer types remains scant. Here we report that the expression level of HDAC10 was significantly lower in patients exhibiting lymph node metastasis compared with that in patients lacking lymph node metastasis in human cervical squamous cell carcinoma. Forced expression of HDAC10 in cervical cancer cells significantly inhibited cell motility and invasiveness in vitro and metastasis in vivo. Mechanistically, HDAC10 suppresses expression of matrix metalloproteinase (MMP) 2 and 9 genes, which are known to be critical for cancer cell invasion and metastasis. At the molecular level, HDAC10 binds to MMP2 and -9 promoter regions, reduces the histone acetylation level, and inhibits the binding of RNA polymerase II to these regions. Furthermore, an HDAC10 mutant lacking histone deacetylase activity failed to mimic the functions of full-length protein. These results identify a critical role of HDAC10 in suppression of cervical cancer metastasis, underscoring the importance of developing isoform-specific HDAC inhibitors for treatment of certain cancer types such as cervical squamous cell carcinoma. PMID:23897811

Song, Chenlin; Zhu, Songcheng; Wu, Chuanyue; Kang, Jiuhong

2013-09-27

24

HDAC2 blockade by nitric oxide and histone deacetylase inhibitors reveals a common target in Duchenne muscular dystrophy treatment  

PubMed Central

The overlapping histological and biochemical features underlying the beneficial effect of deacetylase inhibitors and NO donors in dystrophic muscles suggest an unanticipated molecular link among dystrophin, NO signaling, and the histone deacetylases (HDACs). Higher global deacetylase activity and selective increased expression of the class I histone deacetylase HDAC2 were detected in muscles of dystrophin-deficient MDX mice. In vitro and in vivo siRNA-mediated down-regulation of HDAC2 in dystrophic muscles was sufficient to replicate the morphological and functional benefits observed with deacetylase inhibitors and NO donors. We found that restoration of NO signaling in vivo, by adenoviral-mediated expression of a constitutively active endothelial NOS mutant in MDX muscles, and in vitro, by exposing MDX-derived satellite cells to NO donors, resulted in HDAC2 blockade by cysteine S-nitrosylation. These data reveal a special contribution of HDAC2 in the pathogenesis of Duchenne muscular dystrophy and indicate that HDAC2 inhibition by NO-dependent S-nitrosylation is important for the therapeutic response to NO donors in MDX mice. They also define a common target for independent pharmacological interventions in the treatment of Duchenne muscular dystrophy.

Colussi, Claudia; Mozzetta, Chiara; Gurtner, Aymone; Illi, Barbara; Rosati, Jessica; Straino, Stefania; Ragone, Gianluca; Pescatori, Mario; Zaccagnini, Germana; Antonini, Annalisa; Minetti, Giulia; Martelli, Fabio; Piaggio, Giulia; Gallinari, Paola; Steinkuhler, Christian; Clementi, Emilio; Dell'Aversana, Carmela; Altucci, Lucia; Mai, Antonello; Capogrossi, Maurizio C.; Puri, Pier Lorenzo; Gaetano, Carlo

2008-01-01

25

Design and synthesis of novel and highly-active pan-histone deacetylase (pan-HDAC) inhibitors.  

PubMed

Histone deacetylase (HDAC) inhibitions are known to elicit anticancer effects. We designed and synthesized several HDAC inhibitors. Among these compounds, compound 40 exhibited a more than 10-fold stronger inhibitory activity compared with that of suberoylanilide hydroxamic acid (SAHA) against each human HDAC isozyme in vitro (IC50 values of 40: HDAC1, 0.0038?M; HDAC2, 0.0082?M; HDAC3, 0.015?M; HDAC8, 0.0060?M; HDAC4, 0.058?M; HDAC9, 0.0052?M; HDAC6, 0.058?M). The dose of the administered HDAC inhibitors that contain hydroxamic acid as the zinc-binding group may be reduced by 40. Because the carbostyril subunit is a time-tested structural component of drugs and biologically active compounds, 40 most likely exhibits good absorption, distribution, metabolism, excretion, and toxicity (ADMET). Thus, compound 40 is expected to be a promising therapeutic agent or chemical tool for the investigation of life process. PMID:24864038

Tashima, Toshihiko; Murata, Hiroaki; Kodama, Hidehiko

2014-07-15

26

The histone deacetylase HDAC3 is essential for Purkinje cell function, potentially complicating the use of HDAC inhibitors in SCA1.  

PubMed

Spinocerebellar ataxia type 1 (SCA1) is an incurable neurodegenerative disease caused by a pathogenic glutamine repeat expansion in the protein ataxin-1 (ATXN1). One likely mechanism mediating pathogenesis is excessive transcriptional repression induced by the expanded ATXN-1. Because ATXN1 binds HDAC3, a Class I histone deacetylase (HDAC) that we have found to be required for ATXN1-induced transcriptional repression, we tested whether genetically depleting HDAC3 improves the phenotype of the SCA1 knock-in mouse (SCA1(154Q/2Q)), the most physiologically relevant model of SCA1. Given that HDAC3 null mice are embryonic lethal, we used for our analyses a combination of HDAC3 haploinsufficient and Purkinje cell (PC)-specific HDAC3 null mice. Although deleting a single allele of HDAC3 in the context of SCA1 was insufficient to improve cerebellar and cognitive deficits of the disease, a complete loss of PC HDAC3 was highly deleterious both behaviorally, with mice showing early onset ataxia, and pathologically, with progressive histologic evidence of degeneration. Inhibition of HDAC3 may yet have a role in SCA1 therapy, but our study provides cautionary evidence that this approach could produce untoward effects. Indeed, the neurotoxic consequences of HDAC3 depletion could prove relevant, wherever pharmacologic inhibition of HDAC3 is being contemplated, in disorders ranging from cancer to neurodegeneration. PMID:24594842

Venkatraman, Anand; Hu, Yuan-Shih; Didonna, Alessandro; Cvetanovic, Marija; Krbanjevic, Aleksandar; Bilesimo, Patrice; Opal, Puneet

2014-07-15

27

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

28

Effects of Alcohol on Histone Deacetylase 2 (HDAC2) and the Neuroprotective Role of Trichostatin A (TSA)  

PubMed Central

Background Previous studies have implicated histone deacetylases (HDACs) and HDAC inhibitors (HDIs) such as Trichostatin A (TSA) in the regulation of gene expression during drug addiction. Furthermore, an increase in HDAC activity has been linked to neurodegeneration. Alcohol has also been shown to promote abundant generation of reactive oxygen species (ROS) resulting in oxidative stress. TSA inhibits HDACs and has been shown to be neuroprotective in other neurodegenerative disease models. Although HDACs and HDIs have been associated with drug addiction, there is no evidence of the neurodegenerative role of HDAC2 and neuroprotective role of TSA in alcohol addiction. Therefore, we hypothesize that alcohol modulates HDAC2 through mechanisms involving oxidative stress. Methods In order to test our hypothesis, the human neuronal cell line, SK-N-MC, was treated with different concentrations of alcohol (EtOH); and HDAC2 gene and protein expression were assessed at different time points. Pharmacological inhibition of HDAC2 with TSA was evaluated at the gene level using qRT-PCR and at the protein level using western blot and flow cytometry. ROS production was measured with a fluorescence microplate reader and fluorescence microscopy. Results Our results showed a dose dependent increase of HDAC2 expression with EtOH treatment. Additionally, alcohol significantly induced ROS, and pharmacological inhibition of HDAC2 with TSA was shown to be neuroprotective by significantly inhibiting HDAC2 and ROS. Conclusion These results suggest that EtOH can upregulate HDAC2 through mechanisms involving oxidative stress and HDACs may play an important role in Alcohol Use Disorders (AUDs). Moreover, the use of HDIs may be of therapeutic significance for the treatment of neurodegenerative disorders including AUDs.

Agudelo, Marisela; Gandhi, Nimisha; Saiyed, Zainulabedin; Pichili, Vijaya; Thangavel, Samikkannu; Khatavkar, Pradnya; Yndart-Arias, Adriana; Nair, Madhavan

2011-01-01

29

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

PubMed Central

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

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

2014-01-01

30

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

PubMed

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

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

2014-07-01

31

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

PubMed

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

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

2004-06-01

32

The physiological roles of histone deacetylase (HDAC) 1 and 2: complex co-stars with multiple leading parts.  

PubMed

HDACs (histone deacetylases) 1 and 2 are ubiquitous long-lived proteins, which are often found together in three major multiprotein co-repressor complexes: Sin3, NuRD (nucleosome remodelling and deacetylation) and CoREST (co-repressor for element-1-silencing transcription factor). Although there is a burgeoning number of non-histone proteins within the acetylome, these complexes contain multiple DNA/chromatin-recognition motifs, which, in combination with transcription factors, target HDAC1/2 to chromatin. Their physiological roles should therefore be viewed within the framework of chromatin manipulation. Classically, HDACs were thought to be recruited predominantly by transcriptional repressors to facilitate local histone deacetylation and transcriptional repression. More recently, genome-wide assays have mapped HDAC1/2 and their associated proteins to transcriptionally active loci and have provided alternative context-specific functions, whereby their repressive functions are subtly exerted to balance transcriptional activation and repression. With a few significant exceptions (early embryogenesis, brain development), HDAC1 and HDAC2 are functionally redundant. In most mouse knockout studies, deletion of both enzymes is required in order to produce a substantial phenotype. HDAC1/2 activity has been implicated in the development of numerous tissue and cell types, including heart, skin, brain, B-cells and T-cells. A common feature in all HDAC1/2-knockout, -knockdown and small-molecule inhibitor studies is a reduction in cell proliferation. A generic role in cell cycle progression could be exploited in cancer cells, by blocking HDAC1/2 activity with small-molecule inhibitors, making them potentially useful drug targets. PMID:23697933

Kelly, Richard D W; Cowley, Shaun M

2013-06-01

33

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

34

Histone deacetylase (HDAC) 1 and 2 are Essential for normal T cell Development and Genomic Stability in Mice  

PubMed Central

Histone deacetylase 1 and 2 (HDAC1/2) regulate chromatin structure as the catalytic core of the Sin3A, NuRD and CoREST co-repressor complexes. To better understand the key pathways regulated by HDAC1/2 in the adaptive immune system and inform their exploitation as drug targets, we have generated mice with a T cell specific deletion. Loss of either HDAC1 or HDAC2 alone has little effect, while dual inactivation results in a 5-fold reduction in thymocyte cellularity, accompanied by developmental arrest at the double-negative to double-positive transition. Transcriptome analysis revealed 892 mis-regulated genes in Hdac1/2 knock-out thymocytes, including down-regulation of LAT, Themis and Itk, key components of the T cell receptor (TCR) signalling pathway. Down-regulation of these genes suggests a model in which HDAC1/2 deficiency results in defective propagation of TCR signalling, thus blocking development. Furthermore, mice with a single Hdac2 allele, develop a lethal pathology by 3-months of age, a result of neoplastic transformation of immature T cells in the thymus. Tumor cells become aneuploid, express increased levels of c-Myc and show elevated levels of the DNA damage marker, ?H2AX. These data demonstrate a crucial role for HDAC1/2 in T cell development and the maintenance of genomic stability.

Dovey, Oliver M.; Foster, Charles T.; Conte, Nathalie; Edwards, Sally A.; Edwards, Jennifer M.; Singh, Rajinder; Vasilliou, George; Bradley, Allan; Cowley, Shaun M.

2013-01-01

35

Transport via SLC5A8 with Subsequent Inhibition of Histone Deacetylases HDAC1 and HDAC3 Underlies the Antitumor Activity of 3-Bromopyruvate  

PubMed Central

Background 3-Bromopyruvate is an alkylating agent with antitumor activity. It is currently believed that blockade of ATP production from glycolysis and mitochondria is the primary mechanism responsible for this antitumor effect. The present studies have uncovered a new and novel mechanism for the antitumor activity of 3-bromopyruvate. Methods Transport of 3-bromopyruvate via SLC5A8, a tumor suppressor and a Na+-coupled electrogenic transporter for short-chain monocarboxylates, was studied using a mammalian cell expression and the Xenopus laevis oocyte expression systems. The effect of 3-bromopyruvate on histone deacetylases (HDACs) was monitored using the lysate of the human breast cancer cell line MCF7 and human recombinant HDAC isoforms as the enzyme sources. Cell viability was monitored by FACS analysis and colony formation assay. Acetylation status of histone H4 was evaluated by Western blot. Results 3-Bromopyruvate is a transportable substrate for SLC5A8, with the transport process being Na+-coupled and electrogenic. MCF7 cells do not express SLC5A8 and are not affected by 3-bromopyruvate. However, when transfected with SLC5A8 or treated with inhibitors of DNA methylation, these cells undergo apoptosis in the presence of 3-bromopyruvate. This cell death is associated with inhibition of HDAC1/HDAC3. Studies with different isoforms of human recombinant HDACs identify HDAC1 and HDAC3 as the targets for 3-bromopyruvate. Conclusions 3-Bromopyruvate is transported into cells actively via the tumor suppressor SLC5A8 and the process is energized by an electrochemical Na+ gradient. Ectopic expression of the transporter in MCF7 cells leads to apoptosis, and the mechanism involves inhibition of HDAC1/HDAC3.

Thangaraju, Muthusamy; Karunakaran, Senthil K.; Itagaki, Shiro; Gopal, Elangovan; Elangovan, Selvakumar; Prasad, Puttur D.; Ganapathy, Vadivel

2009-01-01

36

Selective inhibition of histone deacetylase 6 (HDAC6) induces DNA damage and sensitizes transformed cells to anticancer agents.  

PubMed

Histone deacetylase 6 (HDAC6) is structurally and functionally unique among the 11 human zinc-dependent histone deacetylases. Here we show that chemical inhibition with the HDAC6-selective inhibitor tubacin significantly enhances cell death induced by the topoisomerase II inhibitors etoposide and doxorubicin and the pan-HDAC inhibitor SAHA (vorinostat) in transformed cells (LNCaP, MCF-7), an effect not observed in normal cells (human foreskin fibroblast cells). The inactive analogue of tubacin, nil-tubacin, does not sensitize transformed cells to these anticancer agents. Further, we show that down-regulation of HDAC6 expression by shRNA in LNCaP cells enhances cell death induced by etoposide, doxorubicin, and SAHA. Tubacin in combination with SAHA or etoposide is more potent than either drug alone in activating the intrinsic apoptotic pathway in transformed cells, as evidenced by an increase in PARP cleavage and partial inhibition of this effect by the pan-caspase inhibitor Z-VAD-fmk. HDAC6 inhibition with tubacin induces the accumulation of ?H2AX, an early marker of DNA double-strand breaks. Tubacin enhances DNA damage induced by etoposide or SAHA as indicated by increased accumulation of ?H2AX and activation of the checkpoint kinase Chk2. Tubacin induces the expression of DDIT3 (CHOP/GADD153), a transcription factor up-regulated in response to cellular stress. DDIT3 induction is further increased when tubacin is combined with SAHA. These findings point to mechanisms by which HDAC6-selective inhibition can enhance the efficacy of certain anti-cancer agents in transformed cells. PMID:21037108

Namdar, Mandana; Perez, Gisela; Ngo, Lang; Marks, Paul A

2010-11-16

37

Selective inhibition of histone deacetylase 6 (HDAC6) induces DNA damage and sensitizes transformed cells to anticancer agents  

PubMed Central

Histone deacetylase 6 (HDAC6) is structurally and functionally unique among the 11 human zinc-dependent histone deacetylases. Here we show that chemical inhibition with the HDAC6-selective inhibitor tubacin significantly enhances cell death induced by the topoisomerase II inhibitors etoposide and doxorubicin and the pan-HDAC inhibitor SAHA (vorinostat) in transformed cells (LNCaP, MCF-7), an effect not observed in normal cells (human foreskin fibroblast cells). The inactive analogue of tubacin, nil-tubacin, does not sensitize transformed cells to these anticancer agents. Further, we show that down-regulation of HDAC6 expression by shRNA in LNCaP cells enhances cell death induced by etoposide, doxorubicin, and SAHA. Tubacin in combination with SAHA or etoposide is more potent than either drug alone in activating the intrinsic apoptotic pathway in transformed cells, as evidenced by an increase in PARP cleavage and partial inhibition of this effect by the pan-caspase inhibitor Z-VAD-fmk. HDAC6 inhibition with tubacin induces the accumulation of ?H2AX, an early marker of DNA double-strand breaks. Tubacin enhances DNA damage induced by etoposide or SAHA as indicated by increased accumulation of ?H2AX and activation of the checkpoint kinase Chk2. Tubacin induces the expression of DDIT3 (CHOP/GADD153), a transcription factor up-regulated in response to cellular stress. DDIT3 induction is further increased when tubacin is combined with SAHA. These findings point to mechanisms by which HDAC6-selective inhibition can enhance the efficacy of certain anti-cancer agents in transformed cells.

Namdar, Mandana; Perez, Gisela; Ngo, Lang; Marks, Paul A.

2010-01-01

38

Class II histone deacetylases: versatile regulators  

Microsoft Academic Search

Histone acetylation and deacetylation play essential roles in modifying chromatin structure and regulating gene expression in eukaryotes. Histone deacetylases (HDACs) catalyze the deacetylation of lysine residues in the histone N-terminal tails and are found in large multiprotein complexes with transcriptional co-repressors. Human HDACs are grouped into three classes based on their similarity to known yeast factors: class I HDACs are

Eric Verdin; Franck Dequiedt; Herbert G. Kasler

2003-01-01

39

Histone deacetylases and cancer: causes and therapies  

Microsoft Academic Search

Together, histone acetyltransferases and histone deacetylases (HDACs) determine the acetylation status of histones. This acetylation affects the regulation of gene expression, and inhibitors of HDACs have been found to cause growth arrest, differentiation and\\/or apoptosis of many tumours cells by altering the transcription of a small number of genes. HDAC inhibitors are proving to be an exciting therapeutic approach to

Richard A. Rifkind; Victoria M. Richon; Ronald Breslow; Thomas Miller; William K. Kelly; Paul A. Marks

2001-01-01

40

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

41

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.

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

2011-01-01

42

Histone deacetylase (HDAC) inhibitory and antiproliferative activities of phenolic-rich extracts derived from the rhizome of Hydnophytum formicarum Jack.: sinapinic acid acts as HDAC inhibitor  

PubMed Central

Background The rhizome of Hydnophytum formicarum Jack., a medicinal plant known in Thai as Hua-Roi-Roo, has been used in Thai traditional herbal medicine for treatment of cancer. We assessed the ability of its ethanolic and phenolic-rich extracts and its major phenolic compound, sinapinic acid, possessing histone deacetylase (HDAC) inhibitory activity to inhibit proliferation of 5 human cancer cell lines. Methods HeLa cells were used to study HDAC inhibitory activity of the extracts, sinapinic acid, and a well-known HDAC inhibitor sodium butyrate. Five human cancer cell lines and one non-cancer cell line were used to study antiproliferative activities of the plant extracts, sinapinic acid and sodium butyrate, comparatively. Results Results indicated that ethanolic and phenolic-rich extracts of H. formicarum Jack. rhizome possessed both antiproliferative activity and HDAC inhibitory activity in HeLa cells. Sinapinic acid, despite its lower HDAC inhibitory activity than the well-known HDAC inhibitor sodium butyrate, inhibited the growth of HeLa and HT29 cells more effectively than sodium butyrate. However, sinapinic acid inhibited the growth of HCT116 and Jurkat cells less effectively than sodium butyrate. The non-cancer cell line (Vero cells) and breast cancer cell line (MCF-7 cells) appeared to be resistant to both sinapinic acid and sodium butyrate. The growth inhibitory effects of the ethanolic and phenolic-rich extracts and sinapinic acid in HeLa cells were mediated by induction of apoptosis. Conclusions The results of this study support the efficacy of H. formicarum Jack. rhizome ethanolic and phenolic-rich extracts for the treatment of cervical cancer, colon cancer, and T- cell leukemia in an alternative medicine. Further studies of other active ingredients from this plant are needed.

2013-01-01

43

Macrocyclic histone deacetylase inhibitors.  

PubMed

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

2010-01-01

44

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.

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

2012-01-01

45

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

46

Lithium down-regulates histone deacetylase 1 (HDAC1) and induces degradation of mutant huntingtin.  

PubMed

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

2013-12-01

47

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

PubMed

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

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

2013-12-26

48

Molecular dynamics simulation of complex Histones Deacetylase (HDAC) Class II Homo Sapiens with suberoylanilide hydroxamic acid (SAHA) and its derivatives as inhibitors of cervical cancer  

PubMed Central

Cervical cancer is second most common cancer in woman worldwide. Cervical cancer caused by human papillomavirus (HPV) oncogene. Inhibition of histone deacetylase (HDAC) activity has been known as a potential strategy for cancer therapy. SAHA is an HDAC inhibitor that has been used in cancer therapy but still has side effects. SAHA modification proposed to minimize side effects. Triazole attachment on the chain of SAHA has been known to enhance the inhibition ability of SAHA and less toxic. In this study, it will be carried out with molecular dynamic simulations of SAHA modifications consisting ligand 1a, 2a and, 2c to interact with six HDAC in hydrated conditions. To all six HDAC Class II, performed docking with SAHA and a modified inhibitor. The docking results were then carried out molecular dynamics simulations to determine the inhibitor affinities in hydrated conditions. The molecular dynamic simulations results show better affinities of ligand 2c with HDAC 4, 6, and 7 than SAHA itself, and good affinity was also shown by ligand 2a and 1c on HDAC 5 and 9. The results of this study can be a reference to obtain better inhibitors.

Tambunan, Usman Sumo Friend; Bakri, Ridla; Prasetia, Tirtana; Parikesit, Arli Aditya; Kerami, Djati

2013-01-01

49

Histone deacetylase inhibitors: molecular mechanisms of action  

Microsoft Academic Search

This review focuses on the mechanisms of action of histone deacetylase (HDAC) inhibitors (HDACi), a group of recently discovered ‘targeted’ anticancer agents. There are 18 HDACs, which are generally divided into four classes, based on sequence homology to yeast counterparts. Classical HDACi such as the hydroxamic acid-based vorinostat (also known as SAHA and Zolinza) inhibits classes I, II and IV,

W S Xu; R B Parmigiani; P A Marks; PA Marks

2007-01-01

50

Functional Interplay between Histone Demethylase and Deacetylase Enzymes  

Microsoft Academic Search

Histone deacetylase (HDAC) inhibitors are a promising class of anticancer agents for the treatment of solid and hematological malignancies. The precise mechanism by which HDAC inhibitors mediate their effects on tumor cell growth, differentiation, and\\/or apoptosis is the subject of intense research. Previously we described a family of multiprotein complexes that contain histone deacetylase 1\\/2 (HDAC1\\/2) and the histone demeth-

Min Gyu Lee; Christopher Wynder; Daniel A. Bochar; Mohamed-Ali Hakimi; Neil Cooch; Ramin Shiekhattar

2006-01-01

51

Histone deacetylase inhibitor BML-210 induces growth inhibition and apoptosis and regulates HDAC and DAPC complex expression levels in cervical cancer cells.  

PubMed

Histone deacetylase inhibitors (HDACIs) represent a new class of targeted anti-cancer agents and different other diseases, like muscular disorders. A number of studies have shown that extracellular signal-activated kinases can target chromatin-modifying complexes directly and regulate their function. The molecular connection between the dystrophin-associated protein complex (DAPC) and chromatin has been described, by showing that NO signaling regulates histone deacetylase (HDAC) activity and influences gene expression in different cell types. In present study, we investigated HDACs changes in HeLa cells undergoing growth inhibition and apoptosis, caused by HDACI BML-210 and retinoic acid (ATRA). Cell cycle analysis indicated that HeLa cell treatment with 20 and 30 ?M concentration of BML-210 increased the proportion of cells in G0/G1 phase, and caused accumulation in subG1, indicating that the cells are undergoing apoptosis. We determined down-regulation of HDAC 1-5 and 7 after treatment with BML-210. Also, we demonstrated expression of different isoforms of alpha-dystrobrevin (?-DB) and other components of DAPC such as syntrophin, dystrophin, beta-dystrobrevin (?-DB) and NOS in HeLa cells after treatments. We determined changes in protein expression level of dystrophin, NOS1, ?- and ?-DB and in subcellular localization of ?-DB after treatments with BML-210 and ATRA. In conclusion, these results suggest that HDACI BML-210 can inhibit cell growth and induce apoptosis in cervical cancer cells, what correlates with down-regulation of HDAC class I and II and changes in the DAPC expression levels. This can be important for identifying target proteins in DAPC signaling to HDACs, as a target of pharmacological intervention for treatment of muscular dystrophies and other diseases. PMID:23007576

Borutinskaite, Veronika V; Magnusson, Karl-Eric; Navakauskiene, Ruta

2012-12-01

52

A role for histone deacetylase HDAC1 in modulating the transcriptional activity of MyoD: inhibition of the myogenic program  

PubMed Central

The molecular mechanism(s) that are responsible for suppressing MyoD’s transcriptional activities in undifferentiated skeletal muscle cells have not yet been determined. We now show that MyoD associates with a histone deacetylase-1 (HDAC1) in these cells and that this interaction is responsible for silencing MyoD-dependent transcription of endogenous p21 as well as muscle-specific genes. Specifically, we present evidence that HDAC1 can bind directly to MyoD and use an acetylated MyoD as a substrate in vitro, whereas a mutant version of HDAC1 (H141A) can not. Further more, this mutant also fails to repress MyoD-mediated transcription in vivo, and unlike wild-type HDAC1 it can not inhibit myogenic conversion, as judged by confocal microscopy. Finally, we show that an endogenous MyoD can be acetylated upon its conversion to a hypophosphorylated state and only when the cells have been induced to differentiate. These results provide for a model which postulates that MyoD may be co-dependent on HDAC1 and P/CAF for temporally controlling its transcriptional activity before and after the differentiation of muscle cells.

Mal, Asoke; Sturniolo, Michael; Schiltz, R.Louis; Ghosh, Mrinal K.; Harter, Marian L.

2001-01-01

53

Dynamic Structure-Based Pharmacophore Model Development: A New and Effective Addition in the Histone Deacetylase 8 (HDAC8) Inhibitor Discovery  

PubMed Central

Histone deacetylase 8 (HDAC8) is an enzyme involved in deacetylating the amino groups of terminal lysine residues, thereby repressing the transcription of various genes including tumor suppressor gene. The over expression of HDAC8 was observed in many cancers and thus inhibition of this enzyme has emerged as an efficient cancer therapeutic strategy. In an effort to facilitate the future discovery of HDAC8 inhibitors, we developed two pharmacophore models containing six and five pharmacophoric features, respectively, using the representative structures from two molecular dynamic (MD) simulations performed in Gromacs 4.0.5 package. Various analyses of trajectories obtained from MD simulations have displayed the changes upon inhibitor binding. Thus utilization of the dynamically-responded protein structures in pharmacophore development has the added advantage of considering the conformational flexibility of protein. The MD trajectories were clustered based on single-linkage method and representative structures were taken to be used in the pharmacophore model development. Active site complimenting structure-based pharmacophore models were developed using Discovery Studio 2.5 program and validated using a dataset of known HDAC8 inhibitors. Virtual screening of chemical database coupled with drug-like filter has identified drug-like hit compounds that match the pharmacophore models. Molecular docking of these hits reduced the false positives and identified two potential compounds to be used in future HDAC8 inhibitor design.

Thangapandian, Sundarapandian; John, Shalini; Lee, Yuno; Kim, Songmi; Lee, Keun Woo

2011-01-01

54

Histone deacetylase (HDAC) inhibitors in recent clinical trials for cancer therapy  

Microsoft Academic Search

Heritable changes in gene expression that are not based upon alterations in the DNA sequence are defined as epigenetics. The\\u000a most common mechanisms of epigenetic regulation are the methylation of CpG islands within the DNA and the modification of\\u000a amino acids in the N-terminal histone tails. In the last years, it became evident that the onset of cancer and its

Julia M. Wagner; Björn Hackanson; Michael Lübbert; Manfred Jung

2010-01-01

55

Crosstalk between lysine-specific demethylase 1 (LSD1) and histone deacetylases mediates antineoplastic efficacy of HDAC inhibitors in human breast cancer cells  

PubMed Central

Our previous studies demonstrated that lysine-specific demethylase 1 (LSD1) and histone deacetylases (HDACs) closely interact in controlling growth of breast cancer cells. However, the underlying mechanisms are largely unknown. In this study, we showed that knockdown of LSD1 expression (LSD1-KD) by RNAi decreased mRNA levels of HDAC isozymes in triple-negative breast cancer (TNBC) cells. Small interfering RNA (siRNA)-mediated depletion of HDAC5 expression induced the most significant accumulation of H3K4me2, a specific substrate of LSD1. Combined treatment with LSD1 inhibitor, pargyline, and HDAC inhibitor, SAHA (Vorinostat), led to superior growth inhibition and apoptotic death in TNBC cells, but exhibited additive or antagonistic effect on growth inhibition in non-TNBC counterparts or non-tumorigenic breast cells. Additionally, LSD1-KD enhanced SAHA-induced reexpression of a subset of aberrantly silenced genes, such as NR4A1, PCDH1, RGS16, BIK, and E-cadherin whose reexpression may be tumor suppressive. Genome-wide microarray study in MDA-MB-231 cells identified a group of tumor suppressor genes whose expression was induced by SAHA and significantly enhanced by LSD1-KD. We also showed that concurrent depletion of RGS16 by siRNA reduced overall cytotoxicity of SAHA and blocked the reexpression of E-cadherin, CDKN1C and ING1 in LSD1-deficient MDA-MB-231 cells. Furthermore, cotreatment with RGS16 siRNA reversed the downregulation of nuclear factor-kappaB expression induced by combined inhibition of LSD1 and HDACs, suggesting a crucial role of RGS16 in controlling key pathways of cell death in response to combination therapy. Taken together, these results provide novel mechanistic insight into the breast cancer subtype-dependent role of LSD1 in mediating HDAC activity and therapeutic efficacy of HDAC inhibitor.

Vasilatos, Shauna N.; Katz, Tiffany A.; Huang, Yi

2013-01-01

56

Crosstalk between lysine-specific demethylase 1 (LSD1) and histone deacetylases mediates antineoplastic efficacy of HDAC inhibitors in human breast cancer cells.  

PubMed

Our previous studies demonstrated that lysine-specific demethylase 1 (LSD1) and histone deacetylases (HDACs) closely interact in controlling growth of breast cancer cells. However, the underlying mechanisms are largely unknown. In this study, we showed that knockdown of LSD1 expression (LSD1-KD) by RNAi decreased mRNA levels of HDAC isozymes in triple-negative breast cancer (TNBC) cells. Small interfering RNA (siRNA)-mediated depletion of HDAC5 expression induced the most significant accumulation of H3K4me2, a specific substrate of LSD1. Combined treatment with LSD1 inhibitor, pargyline, and HDAC inhibitor, SAHA (Vorinostat), led to superior growth inhibition and apoptotic death in TNBC cells, but exhibited additive or antagonistic effect on growth inhibition in non-TNBC counterparts or non-tumorigenic breast cells. Additionally, LSD1-KD enhanced SAHA-induced reexpression of a subset of aberrantly silenced genes, such as NR4A1, PCDH1, RGS16, BIK, and E-cadherin whose reexpression may be tumor suppressive. Genome-wide microarray study in MDA-MB-231 cells identified a group of tumor suppressor genes whose expression was induced by SAHA and significantly enhanced by LSD1-KD. We also showed that concurrent depletion of RGS16 by siRNA reduced overall cytotoxicity of SAHA and blocked the reexpression of E-cadherin, CDKN1C and ING1 in LSD1-deficient MDA-MB-231 cells. Furthermore, cotreatment with RGS16 siRNA reversed the downregulation of nuclear factor-kappaB expression induced by combined inhibition of LSD1 and HDACs, suggesting a crucial role of RGS16 in controlling key pathways of cell death in response to combination therapy. Taken together, these results provide novel mechanistic insight into the breast cancer subtype-dependent role of LSD1 in mediating HDAC activity and therapeutic efficacy of HDAC inhibitor. PMID:23354309

Vasilatos, Shauna N; Katz, Tiffany A; Oesterreich, Steffi; Wan, Yong; Davidson, Nancy E; Huang, Yi

2013-06-01

57

Butyrate Histone Deacetylase Inhibitors  

PubMed Central

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

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

2012-01-01

58

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.

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

59

Transcriptional repression by histone deacetylases in plants.  

PubMed

Reversible histone acetylation and deacetylation at the N-terminus of histone tails play crucial roles in regulation of eukaryotic gene activity. Acetylation of core histones usually induces an 'open' chromatin structure and is associated with gene activation, whereas deacetylation of histone is often correlated with 'closed' chromatin and gene repression. Histone deacetylation is catalyzed by histone deacetylases (HDACs). A growing number of studies have demonstrated the importance of histone deacetylation/acetylation on genome stability, transcriptional regulation, and development in plants. Furthermore, HDACs were shown to interact with various chromatin remolding factors and transcription factors involved in transcriptional repression in multiple developmental processes. In this review, we summarized recent findings on the transcriptional repression mediated by HDACs in plants. PMID:24658416

Liu, Xuncheng; Yang, Songguang; Zhao, Minglei; Luo, Ming; Yu, Chun-Wei; Chen, Chia-Yang; Tai, Ready; Wu, Keqiang

2014-05-01

60

CD1d induction in solid tumor cells by histone deacetylase inhibitors through inhibition of HDAC1/2 and activation of Sp1  

PubMed Central

CD1d is a MHC class-like molecule that presents glycolipids to natural killer T (NKT) cells, then regulates innate and adaptive immunity. The regulation of CD1d gene expression in solid tumors is still largely unknown. Gene expression can be epigenetically regulated by DNA methylation and histone acetylation. We found that histone deacetylase inhibitors, trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), induced CD1d gene expression in human (A549 and NCI-H292) and mouse (TC-1 and B16/F0) cancer cells. Simultaneous knockdown of HDAC1 and 2 induced CD1d gene expression. Sp1 inhibitor mitramycin A (MTM) blocked TSA- and SAHA-induced CD1d mRNA expression and Sp1 luciferase activity. Co-transfection of GAL4-Sp1 and Fc-luciferase reporters demonstrated that TSA and SAHA induced Sp1 luciferase reporter activity by enhancing Sp1 transactivation activity. The binding of Sp1 to CD1d promoter and histone H3 acetylation on Sp1 sites were increased by TSA and SAHA. These results indicate that TSA and SAHA could up-regulate CD1d expression in tumor cells through inhibition of HDAC1/2 and activation of Sp1.

Yang, Pei-Ming; Lin, Pei-Jie; Chen, Ching-Chow

2012-01-01

61

Lymphocyte Chemotaxis Is Regulated by Histone Deacetylase 6, Independently of Its Deacetylase Activity  

Microsoft Academic Search

In this work, the role of HDAC6, a type II histone deacetylase with tubulin deacetylase activity, in lymphocyte polarity, motility, and transmigration was explored. HDAC6 was localized at dynamic subcellular structures as leading lamelli- podia and the uropod in migrating T-cells. However, HDAC6 activity did not appear to be involved in the polarity of migrating lymphocytes. Overexpression of HDAC6 in

J. Roman Cabrero; Juan M. Serrador; Olga Barreiro; Marõ ´ a Mittelbrunn; Salvador Naranjo-Suarez; Noa Martõ ´ n-Cofreces; Miguel Vicente-Manzanares; Ralph Mazitschek; James E. Bradner; Jesus Avila; Francisco Sanchez-Madrid

2006-01-01

62

Novel Histone Deacetylase Inhibitors.  

National Technical Information Service (NTIS)

The goal of this project is to develop new drugs for cell differentiation therapy of breast cancer. Our central hypothesis is antimalarials and structurally related quinoline compounds are histone deacetylase inhibitors and cause breast tumor cell differe...

J. S. Strobl A. R. Martirosyan

2002-01-01

63

On the Inhibition of Histone Deacetylase 8  

PubMed Central

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

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

2011-01-01

64

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.

Wang, Difei

2009-01-01

65

Limited proteolysis of human histone deacetylase 1  

PubMed Central

Background Histone deacetylase (HDAC) proteins are associated with cell proliferation, differentiation, apoptosis, and cancer. Specifically, HDAC1 is linked with cell growth, a hallmark of cancer formation. HDAC1 is a phosphoprotein and phosphorylation at S421 and S423 promotes HDAC1 enzymatic activity and protein association. While single and double point mutants of HDAC1 at S421 and S423 appear functionally similar, the evidence suggests that HDAC1 is phosphorylated simultaneously at both S421 and S423 in vivo. Additional experiments are necessary to probe the role of double phosphorylation of HDAC1 at S421 and S423. Results To characterize HDAC1 phosphorylation at S421 and S423, limited proteolysis of HDAC1 was performed for the first time. HDAC1 degraded without production of discrete fragments. By performing concentration-dependent proteolysis, HDAC1 double point mutants with disrupted phosphorylation at S421 and S423 displayed different trypsin sensitivities compared to wild type HDAC1. Unexpectedly, HDAC1 single point mutants with disrupted phosphorylation at either S421 or S423 demonstrated protease sensitivity similar to the wild type HDAC1. Conclusion Concentration-dependent proteolysis experiments provide evidence that phosphorylation of S421 and S423 individually contribute to HDAC1 function. In addition, the limited proteolysis experiments support a model where associated proteins promote HDAC1 enzymatic activity, reinforcing the importance of protein interactions in HDAC1 structure and function. Finally, because HDAC1 does not display distinct regions of protease sensitivity, the proteolysis studies suggest that HDAC1 comprises inter-related structural regions.

Kamath, Nayana; Karwowska-Desaulniers, Paulina; Pflum, Mary Kay H

2006-01-01

66

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

PubMed

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

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

2013-01-01

67

Interaction of Histone Acetylases and Deacetylases In Vivo  

Microsoft Academic Search

Having opposing enzymatic activities, histone acetylases (HATs) and deacetylases affect chromatin and regulate transcription. The activities of the two enzymes are thought to be balanced in the cell by an unknown mechanism that may involve their direct interaction. Using fluorescence resonance energy transfer analysis, we demonstrated that the acetylase PCAF and histone deacetylase 1 (HDAC1) are in close spatial proximity

Satoshi Yamagoe; Tomohiko Kanno; Yuka Kanno; Shigakazu Sasaki; Richard M. Siegel; Michael J. Lenardo; Glen Humphrey; Yonghong Wang; Yoshihiro Nakatani; Bruce H. Howard; Keiko Ozato

2003-01-01

68

The SMRT and N-CoR Corepressors Are Activating Cofactors for Histone Deacetylase 3  

Microsoft Academic Search

Repression of gene transcription is linked to regulation of chromatin structure through deacetylation of core histone amino-terminal tails. This action is mediated by histone deacetylases (HDACs) that function within active multiprotein complexes directed to the promoters of repressed genes. In vivo, HDAC3 forms a stable complex with the SMRT corepressor. The SMRT-HDAC3 complex exhibits histone deacetylase activity, whereas recombinant HDAC3

MATTHEW G. GUENTHER; ORR BARAK; MITCHELL A. LAZAR

2001-01-01

69

SAP30, a Novel Protein Conserved between Human and Yeast, Is a Component of a Histone Deacetylase Complex  

Microsoft Academic Search

Histone acetylation plays a key role in the regulation of eukaryotic gene expression. Recently, histone acetylation and deacetylation were found to be catalyzed by structurally distinct, multisubunit complexes that mediate, respectively, activation and repression of transcription. Here, we identify SAP30 as a novel component of the human histone deacetylase complex that includes Sin3, the histone deacetylases HDAC1 and HDAC2, histone

Yi Zhang; Zu-Wen Sun; Rabah Iratni; Hediye Erdjument-Bromage; Paul Tempst; Michael Hampsey; Danny Reinberg

1998-01-01

70

Hepatic steatosis in transgenic mice overexpressing human histone deacetylase 1  

SciTech Connect

It is generally thought that histone deacetylases (HDACs) play important roles in the transcriptional regulation of genes. However, little information is available concerning the specific functions of individual HDACs in disease states. In this study, two transgenic mice lines were established which harbored the human HDAC1 gene. Overexpressed HDAC1 was detected in the nuclei of transgenic liver cells, and HDAC1 enzymatic activity was significantly higher in the transgenic mice than in control littermates. The HDAC1 transgenic mice exhibited a high incidence of hepatic steatosis and nuclear pleomorphism. Molecular studies showed that HDAC1 may contribute to nuclear pleomorphism through the p53/p21 signaling pathway.

Wang, Ai-Guo [Laboratory of Human Genomics, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806 (Korea, Republic of); Seo, Sang-Beom [Department of Life Science, College of Natural Sciences, Chung-Ang University, Seoul 156-756 (Korea, Republic of); Moon, Hyung-Bae [Department of Pathology, School of Medicine, Institute of Medical Science, Wonkwang University, Iksan, Jeonbuk 570-749 (Korea, Republic of); Shin, Hye-Jun [Laboratory of Human Genomics, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806 (Korea, Republic of); Kim, Dong Hoon [Department of Oral Biochemistry, College of Dentistry, Chonnam National University, Gwangju 500-757 (Korea, Republic of); Kim, Jin-Man [Department of Bioscience and Biotechnology, Institute of Bioscience, Sejong University, 98 Kunja-dong, Kwangjin-gu, Seoul 143-747 (Korea, Republic of); Lee, Tae-Hoon [Department of Pathology, College of Medicine, Chungnam National University, Daejeon 301-131 (Korea, Republic of); Kwon, Ho Jeong [Department of Oral Biochemistry, College of Dentistry, Chonnam National University, Gwangju 500-757 (Korea, Republic of); Yu, Dae-Yeul [Laboratory of Human Genomics, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806 (Korea, Republic of)]. E-mail: dyyu10@kribb.re.kr; Lee, Dong-Seok [Laboratory of Human Genomics, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806 (Korea, Republic of)]. E-mail: lee10@kribb.re.kr

2005-05-06

71

Discovery of histone deacetylase 8 selective inhibitors  

PubMed Central

We have developed an efficient method for synthesizing candidate histone deacetylase (HDAC) inhibitors in 96-well plates, which are used directly in high-throughput screening. We selected building blocks having hydrazide, aldehyde and hydroxamic acid functionalities. The hydrazides were coupled with different aldehydes in DMSO. The resulting products have the previously identified ‘cap/linker/biasing element’ structure known to favor inhibition of HDACs. These compounds were assayed without further purification. HDAC8-selective inhibitors were discovered from this novel collection of compounds.

Tang, Weiping; Luo, Tuoping; Greenberg, Edward F.; Bradner, James E.; Schreiber, Stuart L.

2012-01-01

72

Non-hydroxamate histone deacetylase inhibitors.  

PubMed

A number of histone deacetylase (HDAC) inhibitors have been developed as anticancer agents and most of them are hydroxamic acid derivatives, typified by suberoylanilide hydroxamic acid (SAHA), Trichostatin A (TSA) and NVP-LAQ824. However, hydroxamic acids have been associated with poor pharmacokinetics and severe toxicity. In addition, although isozyme-selective HDAC inhibitors are considered useful not only as tools for probing the biology of an enzyme but as drugs with low toxicity, many of the hydroxamate HDAC inhibitors do not distinguish well among the HDAC isozymes. Thus, there has been considerable interest in developing non-hydroxamate HDAC inhibitors. To date, small fatty acids, o-aminoanilides, electrophilic ketones, N-formyl hydroxylamines, thiols and mercaptoamides have been reported as non-hydroxamate HDAC inhibitors, and some of them show antiproliferative activity comparable to hydroxamates. Interestingly, hydroxamate HDAC inhibitors such as SAHA and TSA do not discriminate well among the HDAC isozymes whereas many non-hydroxamate HDAC inhibitors have shown selectivity. These non-hydroxamate HDAC inhibitors should pave the way for the development of tools for biological research and new medicines with few side effects. In this review, we introduce non-hydroxamate HDAC inhibitors describing their design, enzyme inhibition, cancer cell growth inhibition and isozyme selectivity. PMID:16305476

Suzuki, Takayoshi; Miyata, Naoki

2005-01-01

73

Discovery of pyrimidyl-5-hydroxamic acids as new potent histone deacetylase inhibitors.  

PubMed

A series of pyrimidyl-5-hydroxamic acids was prepared for evaluation as inhibitors of histone deacetylase (HDAC). Amino-2-pyrimidinyl can be used as a linker to provide HDAC inhibitors of good enzymatic potency. PMID:15922843

Angibaud, Patrick; Arts, Janine; Van Emelen, Kristof; Poncelet, Virginie; Pilatte, Isabelle; Roux, Bruno; Van Brandt, Sven; Verdonck, Marc; De Winter, Hans; Ten Holte, Peter; Marien, Ann; Floren, Wim; Janssens, Boudewijn; Van Dun, Jacky; Aerts, An; Van Gompel, Jacky; Gaurrand, Sandrine; Queguiner, Laurence; Argoullon, Jean-Michel; Van Hijfte, Luc; Freyne, Eddy; Janicot, Michel

2005-06-01

74

Histone deacetylase inhibitors (HDACIs): multitargeted anticancer agents  

PubMed Central

Histone deacetylase (HDAC) inhibitors are an emerging class of therapeutics with potential as anticancer drugs. The rationale for developing HDAC inhibitors (and other chromatin-modifying agents) as anticancer therapies arose from the understanding that in addition to genetic mutations, epigenetic changes such as dysregulation of HDAC enzymes can alter phenotype and gene expression, disturb homeostasis, and contribute to neoplastic growth. The family of HDAC inhibitors is large and diverse. It includes a range of naturally occurring and synthetic compounds that differ in terms of structure, function, and specificity. HDAC inhibitors have multiple cell type-specific effects in vitro and in vivo, such as growth arrest, cell differentiation, and apoptosis in malignant cells. HDAC inhibitors have the potential to be used as monotherapies or in combination with other anticancer therapies. Currently, there are two HDAC inhibitors that have received approval from the US FDA for the treatment of cutaneous T-cell lymphoma: vorinostat (suberoylanilide hydroxamic acid, Zolinza) and depsipeptide (romidepsin, Istodax). More recently, depsipeptide has also gained FDA approval for the treatment of peripheral T-cell lymphoma. Many more clinical trials assessing the effects of various HDAC inhibitors on hematological and solid malignancies are currently being conducted. Despite the proven anticancer effects of particular HDAC inhibitors against certain cancers, many aspects of HDAC enzymes and HDAC inhibitors are still not fully understood. Increasing our understanding of the effects of HDAC inhibitors, their targets and mechanisms of action will be critical for the advancement of these drugs, especially to facilitate the rational design of HDAC inhibitors that are effective as antineoplastic agents. This review will discuss the use of HDAC inhibitors as multitargeted therapies for malignancy. Further, we outline the pharmacology and mechanisms of action of HDAC inhibitors while discussing the safety and efficacy of these compounds in clinical studies to date.

Ververis, Katherine; Hiong, Alison; Karagiannis, Tom C; Licciardi, Paul V

2013-01-01

75

Histone deacetylase 6 regulates estrogen receptor alpha in uterine leiomyoma.  

PubMed

Histone deacetylase 6 (HDAC) 6 is a regulatory factor in the endocrine traffic network that controls growth factor receptor stability. Histone deacetylase 6 expression and its pathogenic role in the uterine leiomyoma have not been studied. Here, we demonstrated that there was a consistent pattern of increasing HDAC6 and estrogen receptor (ER) ? expression in leiomyoma samples. For all individual cases, expression of HDAC6 in the normal myometrium or leiomyoma positively correlated with ER? expression. The spearman's rho (?) was .53 (P = .008) between HDAC6 and ER? in normal myometrium and, more significantly, the spearman rho was .80 (P < .001) between HDAC6 and ER? in leiomyoma. In ELT-3 leiomyoma cells, silencing HDAC6 expression substantially reduced ER? expression, lowered estrogen response, and inhibited ELT-3 cell growth. Our results, taken together, are the first to provide experimental evidence suggesting that HDAC6 may be an essential molecular therapeutic target in controlling leiomyoma growth. PMID:21421902

Wei, Lin-Hung; Torng, Pao-Ling; Hsiao, Sheng-Mou; Jeng, Yung-Ming; Chen, Min-Wei; Chen, Chi-An

2011-08-01

76

Structural biasing elements for in-cell histone deacetylase paralog selectivity.  

PubMed

We use the structural dissection of two 1,3-dioxanes with in-cell histone deacetylase (HDAC) paralog selectivity to identify key elements for selective HDAC inhibitors. We demonstrate that o-aminoanilides are inactive toward HDAC6 while apparently inhibiting deacetylases that act upon histone substrates. This finding has important clinical implications for the development of HDAC inhibitor-based treatments that do not interfere with microtubule dynamics associated with HDAC6. We also show that suberoylanilide hydroxamic acid (SAHA) alone is a nonparalog-selective HDAC inhibitor and that the 1,3-dioxane diversity appended to SAHA is essential for HDAC6 paralog selectivity. PMID:12733869

Wong, Jason C; Hong, Roger; Schreiber, Stuart L

2003-05-14

77

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

78

Histone Deacetylase Inhibitors and Methods of Use.  

National Technical Information Service (NTIS)

Disclosed are methods of treating an acute myeloid leukemia patient of cytogenetic subgroups having increased histone deacetylase recruitment by administering a histone deacetylase inhibitor to the patient.

O. Odenike

2005-01-01

79

Factors affecting the substrate specificity of histone deacetylases  

Microsoft Academic Search

Histone deacetylases (HDACs) catalyze the deacetylation of ?-acetyl-lysine residues within the N-terminal tail of core histones and thereby mediate changes in the chromatin structure and regulate gene expression in eukaryotic cells. So far, surprisingly little is known about the substrate specificities of different HDACs. Here, we prepared a library of fluorogenic tripeptidic substrates of the general format Ac-P-2-P-1-Lys(Ac)-MCA (P-1, P-2=all

Daniel Riester; Christian Hildmann; Sylvia Grünewald; Thomas Beckers; Andreas Schwienhorst

2007-01-01

80

Posttranslational modifications of histone deacetylases: implications for cardiovascular diseases.  

PubMed

Posttranslational modification (PTM) is a term that implies dynamic modification of proteins after their translation. PTM is involved not only in homeostasis but also in pathologic conditions related to diverse diseases. Histone deacetylases (HDACs), which are known as transcriptional regulators, are one example of posttranslational modifiers with diverse roles in human pathophysiology, including cardiovascular diseases. In experimental models, HDAC inhibitors are beneficial in supraventricular arrhythmia, myocardial infarction, cardiac remodeling, hypertension, and fibrosis. In addition, HDACs are closely related to other vascular diseases such as neointima formation, atherosclerosis, and vascular calcification. Currently, HDACs are classified into four different classes. The class IIa HDACs work as transcriptional regulators mainly by direct association with other transcription factors to their target binding elements in a phosphorylation-dependent manner. Class I HDACs, by contrast, have much greater enzymatic activity than the class II HDACs and target various non-histone proteins as well as the histone-core complex. Class I HDACs undergo PTMs such as phosphorylation, sumoylation, and S-nitrosylation. Considering the growing evidence for the role of HDACs in cardiovascular diseases, the PTMs of the HDACs themselves as well as HDAC-mediated PTM of their targets should be considered for future potential therapeutic targets. In this review, we discuss 1) the roles of each HDAC in specific cardiovascular diseases and 2) the PTM of HDACs, 3) and the implications of such modifications for cardiovascular diseases. PMID:24594235

Eom, Gwang Hyeon; Kook, Hyun

2014-08-01

81

Histone Deacetylase Complexes Promote Trinucleotide Repeat Expansions  

PubMed Central

Expansions of DNA trinucleotide repeats cause at least 17 inherited neurodegenerative diseases, such as Huntington's disease. Expansions can occur at frequencies approaching 100% in affected families and in transgenic mice, suggesting that specific cellular proteins actively promote (favor) expansions. The inference is that expansions arise due to the presence of these promoting proteins, not their absence, and that interfering with these proteins can suppress expansions. The goal of this study was to identify novel factors that promote expansions. We discovered that specific histone deacetylase complexes (HDACs) promote CTG•CAG repeat expansions in budding yeast and human cells. Mutation or inhibition of yeast Rpd3L or Hda1 suppressed up to 90% of expansions. In cultured human astrocytes, expansions were suppressed by 75% upon inhibition or knockdown of HDAC3, whereas siRNA against the histone acetyltransferases CBP/p300 stimulated expansions. Genetic and molecular analysis both indicated that HDACs act at a distance from the triplet repeat to promote expansions. Expansion assays with nuclease mutants indicated that Sae2 is one of the relevant factors regulated by Rpd3L and Hda1. The causal relationship between HDACs and expansions indicates that HDACs can promote mutagenesis at some DNA sequences. This relationship further implies that HDAC3 inhibitors being tested for relief of expansion-associated gene silencing may also suppress somatic expansions that contribute to disease progression.

Gleeson, Olive; Kirkham-McCarthy, Lucy; Mertz, Tony; Lahue, Robert S.

2012-01-01

82

Modulation of immunoglobulin gene conversion frequency and distribution by the histone deacetylase HDAC2 in chicken DT40  

Microsoft Academic Search

Modifications of histones are reportedly associated with the regulation of immunoglobulin (Ig) gene diversification mechanisms, but the extent of their involvement in promoting sequence alterations at the Ig variable (V) regions still remains to be elucidated. We have previously demonstrated that Ig gene conversion in the B cell line DT40 is accompanied by the local hyper- acetylation of histones, and

Waka Lin; Shu-ichi Hashimoto; Hidetaka Seo; Takehiko Shibata; Kunihiro Ohta

2008-01-01

83

The Human Histone Deacetylase Family  

Microsoft Academic Search

Since the identification of the first histone deacetylase (Taunton et al., Science 272, 408–411), several new members have been isolated. They can loosely be separated into entities on the basis of their similarity to various yeast histone deacetylases. The first class is represented by its closeness to the yeast Rpd3-like proteins, and the second most recently discovered class has similarities

Steven G. Gray; Tomas J. Ekström

2001-01-01

84

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

85

Multiple N-CoR complexes contain distinct histone deacetylases.  

PubMed

N-CoR (nuclear receptor corepressor) is a corepressor for multiple transcription factors including unliganded thyroid hormone receptors (TRs). In vitro, N-CoR can interact with the Sin3 corepressor, which in turn binds to the histone deacetylase Rpd3 (HDAC1), predicting the existence of a corepressor complex containing N-CoR, Sin3, and histone deacetylase. However, previous biochemical studies of endogenous Sin3 complexes have failed to find an N-CoR association. Xenopus laevis eggs and oocytes contain all of the necessary components for transcriptional repression by unliganded TRs. In this study, we report the biochemical fractionation of three novel macromolecular complexes containing N-CoR, two of which possess histone deacetylase activity, from Xenopus egg extract. One complex contains Sin3, Rpd3, and RbAp48; the second complex contains a Sin3-independent histone deacetylase; and the third complex lacks histone deacetylase activity. This study describes the first biochemical isolation of endogenous N-CoR-containing HDAC complexes and illustrates that N-CoR associates with distinct histone deacetylases that are both dependent and independent of Sin3. Immunoprecipitation studies show that N-CoR binds to unliganded TR expressed in the frog oocyte, confirming that N-CoR complexes are involved in repression by unliganded TR. These results suggest that N-CoR targets transcriptional repression of specific promoters through at least two distinct histone deacetylase pathways. PMID:11254656

Jones, P L; Sachs, L M; Rouse, N; Wade, P A; Shi, Y B

2001-03-23

86

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.

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

2012-01-01

87

Activity of histone deacetylase inhibitors and an Aurora kinase inhibitor in BCR-ABL-expressing leukemia cells: Combination of HDAC and Aurora inhibitors in BCR-ABL-expressing cells  

PubMed Central

Background The use of imatinib, an ABL tyrosine kinase inhibitor, has led to a dramatic change in the management of BCR-ABL-positive leukemia patients. However, resistance to imatinib mediated by mutations in the BCR-ABL domain has become a major problem in the treatment of these patients. Methods In the present study, we examined the activity of histone deacetylase (HDAC) inhibitors in combination with an Aurora kinase inhibitor in BCR-ABL-expressing cells. Results We found the HDAC inhibitors vorinostat and/or pracinostat (SB939) induced apoptosis in BCR-ABL-expressing cells. Additionally, HDAC inhibitors reduced levels of Aurora A and B protein. An Aurora kinase inhibitor, tozasertib (VX-680), inhibited growth, promoted pro-apoptotic activity, reduced the phosphorylation of BCR-ABL and Crk-L, and activated caspase-3 and poly (ADP-ribose) polymerase (PARP) in BCR-ABL-positive cells. Moreover, after treatment with tozasertib, HDAC protein expression was decreased. Combination of vorinostat or pracinostat with tozasertib had a synergistic inhibitory effect on the proliferation of T315I cells. Phosphorylation of Crk-L decreased, and PARP activation increased after treatment with vorinostat or pracinostat and tozasertib. Moreover, combination of vorinostat or pracinostat and tozasertib significantly increased the extent of apoptosis in primary chronic myeloid leukemia cells. Conclusions This study demonstrated that combination of HDAC and Aurora inhibitors was highly effective against BCR-ABL-expressing cells.

2013-01-01

88

Histone deacetylase inhibitors in multiple myeloma  

PubMed Central

Novel drugs such as bortezomib and high-dose chemotherapy combined with stem cell transplantation improved the outcome of multiple myeloma patients in the past decade. However, multiple myeloma often remains incurable due to the development of drug resistance governed by the bone marrow microenvironment. Therefore targeting new pathways to overcome this resistance is needed. Histone deacetylase (HDAC) inhibitors represent a new class of anti-myeloma agents. Inhibiting HDACs results in histone hyperacetylation and alterations in chromatine structure, which, in turn, cause growth arrest differentiation and/or apoptosis in several tumor cells. Here we summarize the molecular actions of HDACi as a single agent or in combination with other drugs in different in vitro and in vivo myeloma models and in (pre-)clinical trials.

Deleu, Sarah; Menu, Eline; Valckenborgh, Els Van; Van Camp, Ben; Fraczek, Joanna; Vande Broek, Isabelle; Rogiers, Vera; Vanderkerken, Karin

2009-01-01

89

Histone deacetylase inhibitors: Signalling towards p21 cip1\\/waf1  

Microsoft Academic Search

Chromatin-modifying enzymes such as histone deacetylases (HDAC) facilitate a closed chromatin structure and hence transcriptional repression. HDAC are commonly affected in human cancer diseases. Thus, inhibition of HDAC represents a novel therapeutic approach. Several studies have shown that HDAC inhibitors strongly activate the expression of the cyclin-dependent kinase inhibitor p21cip1\\/waf1 through (i) enhanced histone acetylation around the p21cip1\\/waf1 promoter and

Matthias Ocker; Regine Schneider-Stock

2007-01-01

90

Histone deacetylase inhibitors and anticancer therapy.  

PubMed

Recent reports have shown that pharmacological manipulation of chromatin remodeling by histone deacetylase (HDAC) inhibitors, might develop into a potent and specific strategy for the treatment of cancer. Alterations in histone acetylation may lead to changes in chromatin structure and transcriptional dysregulation of genes that are implicated in controlling either cell cycle progression or pathways regulating cell differentiation and/or apoptosis. Dimethyl sulphoxide was one of the first chemicals to be identified as an inducer of transformed cell differentiation. In the class of HDAC inhibitors, now included a short-chain fatty acids, such as 4-phenylbutyrate and valporic acid, hydroxamic acids, such as suberoylanilide hydroxamic acid (SAHA), pyroxamide, trichostatin A, oxamflatin and CHAPSs, cyclic tetrapeptides, such as trapoxin, apicidin and depsipeptide-also known as FK-228 or FR 901228, and benzamides, such as MS-275. First clinical studies have shown that histone hyperacetylation can be achieved safely in humans and that treatment of cancer with such agents seems to become possible. Thus, HDAC inhibitors remains one of the most promising class of new anticancer agents. Further studies are needed in order to delineate the optimal dosage, the duration of therapy and possibly the efficacy of other agents able to synergize with HDAC inhibitors in the fight against cancer. PMID:12678732

Kouraklis, G; Theocharis, S

2002-07-01

91

Histone deacetylase inhibitors: mechanism of action and therapeutic use in cancer  

Microsoft Academic Search

Histone deacetylases (HDACs) remove the acetyl groups of lysine residues of histone tails leading to chromatin compaction\\u000a and transcriptional repression. In addition, HDACs can also influence transcription-independent events such as mitosis or\\u000a deoxyribonucleic acid (DNA) repair and deacetylate nonhistone proteins involved in cell proliferation and death, altering\\u000a their function. Histone deacetylase inhibitors (HDACi) constitute a promising treatment for cancer therapy

Olaia Martínez-Iglesias; Lidia Ruiz-Llorente; Ruth Sánchez-Martínez; Laura García; Alberto Zambrano; Ana Aranda

2008-01-01

92

Suppression of caspase-11 expression by histone deacetylase inhibitors  

SciTech Connect

It has been well documented that histone deacetylase inhibitors suppress inflammatory gene expression. Therefore, we investigated whether histone deacetylase inhibitors modulate the expression of caspase-11 that is known as an inducible caspase regulating both inflammation and apoptosis. In the present study, we show that sodium butyrate and trichostatin A, two structurally unrelated inhibitors of histone deacetylase (HDAC), effectively suppressed the induction of caspase-11 in mouse embryonic fibroblasts stimulated with lipopolysaccharides. Sodium butyrate inhibited the activation of upstream signaling events for the caspase-11 induction such as activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase, degradation of inhibitor of {kappa}B, and activation of nuclear factor-{kappa}B. These results suggest that the HDAC inhibitor suppressed cytosolic signaling events for the induction of caspase-11 by inhibiting the deacetylation of non-histone proteins.

Heo, Hyejung; Yoo, Lang [Department of Molecular Biology, Sejong University, 98 Gunja-dong, Gwangjin-gu, Seoul 143-747 (Korea, Republic of); Shin, Ki Soon [Department of Biology and Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul 130-701 (Korea, Republic of); Kang, Shin Jung [Department of Molecular Biology, Sejong University, 98 Gunja-dong, Gwangjin-gu, Seoul 143-747 (Korea, Republic of)], E-mail: sjkang@sejong.ac.kr

2009-01-02

93

Histone deacetylase: a potential therapeutic target for fibrotic disorders.  

PubMed

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 the past several years, the role of HDACs in cancer initiation and progression, as well as the therapeutic effects of HDAC inhibitors in various types of cancer, has been well studied. Recent studies indicated that HDAC activity is also associated with the development and progression of some chronic diseases characterized by fibrosis, including chronic kidney disease, cardiac hypertrophy, and idiopathic pulmonary fibrosis. Here, we review what is known about HDACs in the progression of tissue fibrosis and the potential applications of HDAC inhibitors in the treatment of disorders associated with fibroblast activation and proliferation. PMID:20719940

Pang, Maoyin; Zhuang, Shougang

2010-11-01

94

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

95

Histone Deacetylase: A Potential Therapeutic Target for Fibrotic Disorders  

PubMed Central

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 the past several years, the role of HDACs in cancer initiation and progression, as well as the therapeutic effects of HDAC inhibitors in various types of cancer, has been well studied. Recent studies indicated that HDAC activity is also associated with the development and progression of some chronic diseases characterized by fibrosis, including chronic kidney disease, cardiac hypertrophy, and idiopathic pulmonary fibrosis. Here, we review what is known about HDACs in the progression of tissue fibrosis and the potential applications of HDAC inhibitors in the treatment of disorders associated with fibroblast activation and proliferation.

Pang, Maoyin

2010-01-01

96

Histone deacetylase inhibitors in the treatment of lymphoma.  

PubMed

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

Lemoine, Manuela; Younes, Anas

2010-11-01

97

Lymphocyte Chemotaxis Is Regulated by Histone Deacetylase 6, Independently of Its Deacetylase Activity  

PubMed Central

In this work, the role of HDAC6, a type II histone deacetylase with tubulin deacetylase activity, in lymphocyte polarity, motility, and transmigration was explored. HDAC6 was localized at dynamic subcellular structures as leading lamellipodia and the uropod in migrating T-cells. However, HDAC6 activity did not appear to be involved in the polarity of migrating lymphocytes. Overexpression of HDAC6 in freshly isolated lymphocytes and T-cell lines increased the lymphocyte migration mediated by chemokines and their transendothelial migration under shear flow. Accordingly, the knockdown of HDAC6 expression in T-cells diminished their chemotactic capability. Additional experiments with HDAC6 inhibitors (trichostatin, tubacin), other structural related molecules (niltubacin, MAZ-1391), and HDAC6 dead mutants showed that the deacetylase activity of HDAC6 was not involved in the modulatory effect of this molecule on cell migration. Our results indicate that HDAC6 has an important role in the chemotaxis of T-lymphocytes, which is independent of its tubulin deacetylase activity.

Cabrero, J. Roman; Serrador, Juan M.; Barreiro, Olga; Mittelbrunn, Maria; Naranjo-Suarez, Salvador; Martin-Cofreces, Noa; Vicente-Manzanares, Miguel; Mazitschek, Ralph; Bradner, James E.; Avila, Jesus; Valenzuela-Fernandez, Agustin

2006-01-01

98

Endogenous modulators and pharmacological inhibitors of histone deacetylases in cancer therapy  

Microsoft Academic Search

The class-I histone deacetylases (HDACs) HDAC1 and HDAC2 belong to a family of 11 zinc-dependent human HDACs and are overexpressed in many cancers. Inhibitors of these HDACs now in clinical trials show activity against several types of cancers. This review is focused on recent advances in both clinical and preclinical efforts to understand the basis for the actions of HDACis,

S Spiegel; S Milstien; S Grant

2012-01-01

99

Functional and physical interaction between the histone methyl transferase Suv39H1 and histone deacetylases.  

PubMed

The histone methyl transferase Suv39H1 is involved in silencing by pericentric heterochromatin. It specifically methylates K9 of histone H3, thereby creating a high affinity binding site for HP1 proteins. We and others have shown recently that it is also involved in transcriptional repression by the retinoblastoma protein Rb. Strikingly, both HP1 localisation and repression by Rb also require, at least in part, histone deacetylases. We found here that repression of a heterologous promoter by Suv39H1 is dependent on histone deacetylase activity. However, the enzymatic activity of Suv39H1 is not required, since the N-terminal part is by itself a transcriptional repression domain. Coimmunoprecipitation experiments indicated that Suv39H1 can physically interact with HDAC1, -2 and -3, therefore suggesting that transcriptional repression by Suv39H1 could be the consequence of histone deacetylases recruitment. Consistent with this interpretation, the N-terminal transcriptional repression domain of Suv39H1 bound the so-called 'core histone deacetylase complex', composed of HDAC1, HDAC2 and the Rb-associated proteins RbAp48 and RbAp46. Taken together, our results suggest that a complex containing both the Suv39H1 histone methyl transferase and histone deacetylases could be involved in heterochromatin silencing or transcriptional repression by Rb. PMID:11788710

Vaute, Olivier; Nicolas, Estelle; Vandel, Laurence; Trouche, Didier

2002-01-15

100

Novel amide derivatives as inhibitors of histone deacetylase: Design, synthesis and SAR  

Microsoft Academic Search

Enzymatic inhibition of histone deacetylase (HDAC) activity is emerging as an innovative and effective approach for the treatment of cancer. A series of novel amide derivatives have been synthesized and evaluated for their ability to inhibit human HDACs. Multiple compounds were identified as potent HDAC inhibitors (HDACi), with IC50 values in the low nanomolar (nM) range against enzyme activity in

Victor Andrianov; Vija Gailite; Daina Lola; Einars Loza; Valentina Semenikhina; Ivars Kalvinsh; Paul Finn; Kamille Dumong Petersen; James W. A. Ritchie; Nagma Khan; Anthony Tumber; Laura S. Collins; Sree M. Vadlamudi; Fredrik Björkling; Maxwell Sehested

2009-01-01

101

HDAC4 Does Not Act as a Protein Deacetylase in the Postnatal Murine Brain In Vivo  

PubMed Central

Reversible protein acetylation provides a central mechanism for controlling gene expression and cellular signaling events. It is governed by the antagonistic commitment of two enzymes families: the histone acetyltransferases (HATs) and the histone deacetylases (HDACs). HDAC4, like its class IIa counterparts, is a potent transcriptional repressor through interactions with tissue specific transcription factors via its N-terminal domain. Whilst the lysine deacetylase activity of the class IIa HDACs is much less potent than that of the class I enzymes, HDAC4 has been reported to influence protein deacetylation through its interaction with HDAC3. To investigate the influence of HDAC4 on protein acetylation we employed the immunoaffinity-based AcetylScan proteomic method. We identified many proteins known to be modified by acetylation, but found that the absence of HDAC4 had no effect on the acetylation profile of the murine neonate brain. This is consistent with the biochemical data suggesting that HDAC4 may not function as a lysine deacetylase, but these in vivo data do not support the previous report showing that the enzymatic activity of HDAC3 might be modified by its interaction with HDAC4. To complement this work, we used Affymetrix arrays to investigate the effect of HDAC4 knock-out on the transcriptional profile of the postnatal murine brain. There was no effect on global transcription, consistent with the absence of a differential histone acetylation profile. Validation of the array data by Taq-man qPCR indicated that only protamine 1 and Igfbp6 mRNA levels were increased by more than one-fold and only Calml4 was decreased. The lack of a major effect on the transcriptional profile is consistent with the cytoplasmic location of HDAC4 in the P3 murine brain.

Mielcarek, Michal; Seredenina, Tamara; Stokes, Matthew P.; Osborne, Georgina F.; Landles, Christian; Inuabasi, Linda; Franklin, Sophie A.; Silva, Jeffrey C.; Luthi-Carter, Ruth; Beaumont, Vahri; Bates, Gillian P.

2013-01-01

102

Systemic or Intrahippocampal Delivery of Histone Deacetylase Inhibitors Facilitates Fear Extinction  

Microsoft Academic Search

Several recent studies have shown that chromatin, the DNA–protein complex that packages genomic DNA, has an important function in learning and memory. Dynamic chromatin modification via histone deacetylase (HDAC) inhibitors and histone acetyltransferases may enhance hippocampal synaptic plasticity and hippocampus-dependent memory. Little is known about the effects of HDAC inhibitors on extinction, a learning process through which the ability of

K. Matthew Lattal; Ruth M. Barrett; Marcelo A. Wood

2007-01-01

103

Protected from the inside: Endogenous histone deacetylase inhibitors and the road to cancer  

Microsoft Academic Search

Histone deacetylases (HDACs) play a crucial role in several physiological and pathological cell functions, including cell development and cancer, by deacetylating both histones and others proteins. HDACs belong to a large family of enzymes including Class I, II and IV as well as Class III or sirtuins subfamilies, that undergo a complex transcriptional and post-translational regulation. In current years, antitumor

Lucia Di Marcotullio; Gianluca Canettieri; Paola Infante; Azzura Greco; Alberto Gulino

2011-01-01

104

An Essential Role for Histone Deacetylase 4 in Synaptic Plasticity and Memory Formation  

PubMed Central

Histone deacetylases (HDACs), a family of enzymes involved in epigenetic regulation, have been implicated in the control of synaptic plasticity, as well as learning and memory. Previous work has demonstrated administration of pharmacological histone deacetylase (HDAC) inhibitors, primarily those targeted to Class I HDACs, enhance learning and memory as well as long-term potentiation. However, a detailed understanding of the role of Class II HDACs in these processes remains elusive. Here, we show that selective loss of Hdac4 in brain results in impairments in hippocampal-dependent learning and memory and long-term synaptic plasticity. In contrast, loss of Hdac5 does not impact learning and memory demonstrating unique roles in brain for individual Class II HDACs. These findings suggest that HDAC4 is a crucial positive regulator of learning and memory, both behaviorally and at the cellular level, and that inhibition of Hdac4 activity may have unexpected detrimental effects to these processes.

Kim, Mi-Sung; Akhtar, M. Waseem; Adachi, Megumi; Mahgoub, Melissa; Bassel-Duby, Rhonda; Kavalali, Ege T.; Olson, Eric N.; Monteggia, Lisa M.

2012-01-01

105

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

PubMed

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

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

2008-01-15

106

Prostate Cancer Prevention by Sulforaphane, a Novel Dietary Histone Deacetylase Inhibitor.  

National Technical Information Service (NTIS)

Prostate cancer is the second leading cause of cancer related death in men. To test Sulforaphane (SFN) as a novel histone deacetylases (HDAC) inhibitor and explore the mechanism of SFN protection against prostate cancer, different stage of prostate cancer...

Y. Zhen

2008-01-01

107

RBP1 Recruits Both Histone Deacetylase-Dependent and Independent Repression Activities to Retinoblastoma Family Proteins  

Microsoft Academic Search

Retinoblastoma (RB) tumor suppressor family proteins block cell proliferation in part by repressing certain E2F-specific promoters. Both histone deacetylase (HDAC)-dependent and -independent repression activities are associated with the RB \\

ALBERT LAI; JOSEPH M. LEE; WEN-MING YANG; JAMES A. DECAPRIO; WILLIAM G. KAELIN; EDWARD SETO; PHILIP E. BRANTON

1999-01-01

108

Macrocyclic Peptoid-Peptide Hybrids as Inhibitors of Class I Histone Deacetylases  

PubMed Central

We report the design, synthesis, and biological evaluation of the first macrocyclic peptoid-containing histone deacetylase (HDAC) inhibitors. The compounds selectively inhibit human class I HDAC isoforms in vitro, with no inhibition of the tubulin deacetylase activity associated with class IIb HDAC6 in cultured Jurkat cells. Compared to the natural product apicidin (1), one inhibitor (compound 10) showed equivalent potency against K-562 cells, but was more cytoselective across a panel of cancer cell lines.

2012-01-01

109

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

110

Histone deacetylase induces accelerated maturation in Xenopus laevis oocytes.  

PubMed

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

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

2013-04-01

111

Regulation of Tat Acetylation and Transactivation Activity by the Microtubule-associated Deacetylase HDAC6*  

PubMed Central

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.

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

2011-01-01

112

HDAC6 Deacetylase Activity Is Required for Hypoxia-Induced Invadopodia Formation and Cell Invasion  

PubMed Central

Despite significant progress in the cancer field, tumor cell invasion and metastasis remain a major clinical challenge. Cell invasion across tissue boundaries depends largely on extracellular matrix degradation, which can be initiated by formation of actin-rich cell structures specialized in matrix degradation called invadopodia. Although the hypoxic microenvironment within solid tumors has been increasingly recognized as an important driver of local invasion and metastasis, little is known about how hypoxia influences invadopodia biogenesis. Here, we show that histone deacetylase 6 (HDAC6), a cytoplasmic member of the histone deacetylase family, is a novel modulator of hypoxia-induced invadopodia formation. Hypoxia was found to enhance HDAC6 tubulin deacetylase activity through activation of the EGFR pathway. Activated HDAC6, in turn, triggered Smad3 phosphorylation resulting in nuclear accumulation. Inhibition of HDAC6 activity or knockdown of the protein inhibited both hypoxia-induced Smad3 activation and invadopodia formation. Our data provide evidence that hypoxia influences invadopodia formation in a biphasic manner, which involves the activation of HDAC6 deacetylase activity by EGFR, resulting in enhanced Smad phosphorylation and nuclear accumulation. The identification of HDAC6 as a key participant of hypoxia-induced cell invasion may have important therapeutic implications for the treatment of metastasis in cancer patients.

Arsenault, Dominique; Brochu-Gaudreau, Karine; Charbonneau, Martine; Dubois, Claire M.

2013-01-01

113

Subcellular localization of rice histone deacetylases in organelles.  

PubMed

Histone deacetylases (HDACs) are known to function in the nucleus. Here, we report on the organellar localization of three rice HDACs, OsSIR2b, OsHDAC6, and OsHDAC10. The 35S:OsSIR2b-GFP and 35S:OsHDAC10-GFP constructs were introduced into tobacco BY2 cells. Co-localization analysis of the green fluorescent protein and MitoTracker fluorescent signals in the transformed BY2 cells indicated that OsSIR2b and OsHDAC10 are localized in the mitochondria. Transgenic Arabidopsis lines harboring 35S:OsHDAC6-GFP and 35S:OsHDAC10-GFP constructs were similarly analyzed, revealing that OsHDAC6-GFP is localized exclusively in chloroplasts, whereas OsHDAC10-GFP is localized in both mitochondria and chloroplasts. The presence of OsHDAC6-GFP and OsHDAC10-GFP in chloroplasts was verified by immunodetection. PMID:19505461

Chung, Pil Joong; Kim, Youn Shic; Park, Su-Hyun; Nahm, Baek Hie; Kim, Ju-Kon

2009-07-01

114

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

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

2013-09-20

115

[Structure-activity relationships of histone deacetylase inhibitors].  

PubMed

Among those enzymes that regulate gene expression, histone deacetylases (HDACs) play important roles in cell cycles. Extensive studies were carried out in the field of HDACs and the applications of HDAC inhibitors (HDACIs) as chemotherapeutic interventions for diverse diseases. HDACIs have moved from laboratories to clinic uses. Huge bodies of related research results were well documented and dispersed in literature. According to our understanding, HDACIs can be broadly classified as hydroxamic acids, cyclic tetrapeptides, short chain fatty acids, benzamides and electrophilic ketones. Herein, we are going to review the design and their structure-activity relationships of HDACIs and according to their structural catalogs. PMID:20055127

Tan, Yu-Mei; Huang, Wen-Yuan; Yu, Nie-Fang

2009-10-01

116

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

117

Radioprotection by the histone deacetylase inhibitor phenylbutyrate.  

PubMed

The histone deacetylase inhibitor (HDAC), phenylbutyrate (PB), is a novel anti-tumor agent. Studies have demonstrated that HDAC inhibitors can suppress cutaneous radiation syndrome and stimulate hematopoiesis. The objective of this study was to test the ability of PB treatment to protect against acute gamma-radiation-induced lethality in the DBA/2 mouse model. A 30-day radiation lethality study was used to assess radioprotective capability of PB. Mechanisms were evaluated using western blots, flow cytometry, and the single-cell gel electrophoresis assay. Western blot studies showed that PB treatment acetylated histones in vivo. For radiation protection studies, prophylactic administration of PB (24 h preradiation; 1-50 mg/kg) provided radioprotection against gamma radiation (8-9.5 Gy) and PB demonstrated a DRF of 1.31 (P = 0.001; 95% confidence interval: 1.27, 1.36). When PB (10 mg/kg) was administered post-radiation (4 h), it also provided significant radioprotection at 8.0 Gy radiation (P = 0.022). PB treatment before radiation was associated with significant elevations in neutrophils and platelets following radiation. Results from single-cell gel electrophoresis of peripheral blood leukocytes demonstrated that PB treatment before radiation can attenuate DNA damage and inhibit radiation-induced apoptosis. These results indicate that an HDAC inhibitor like PB has potential as a radiation protector and that mechanisms of action include attenuation of DNA damage and inhibition of apoptosis. PMID:21892632

Miller, Alexandra C; Cohen, Stuart; Stewart, Michael; Rivas, Rafael; Lison, Paul

2011-11-01

118

Characterization of Inhibitor-Resistant Histone Deacetylase Activity in Plant-Pathogenic Fungi  

Microsoft Academic Search

HC-toxin, a cyclic peptide made by the filamentous fungus Cochliobolus carbonum, is an inhibitor of histone deacetylase (HDAC) from many organisms. It was shown earlier that the HDAC activity in crude extracts of C. carbonum is relatively insensitive to HC-toxin as well as to the chemically unrelated HDAC inhibitors trichostatin and D85, whereas the HDAC activity of Aspergillus nidulans is

Dipnath Baidyaroy; Gerald Brosch; Stefan Graessle; Patrick Trojer; Jonathan D. Walton

2002-01-01

119

Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes  

Microsoft Academic Search

Low oxygen tension influences tumor progression by enhancing angiogenesis; and histone deacetylases (HDAC) are implicated in alteration of chromatin assembly and tumorigenesis. Here we show induction of HDAC under hypoxia and elucidate a role for HDAC in the regulation of hypoxia-induced angiogenesis. Overexpressed wild-type HDAC1 downregulated expression of p53 and von Hippel–Lindau tumor suppressor genes and stimulated angiogenesis of human

Myoung Sook Kim; Ho Jeong Kwon; You Mie Lee; Jin Hyen Baek; Jae-Eun Jang; Sae-Won Lee; Eun-Joung Moon; Hae-Sun Kim; Seok-Ki Lee; Hae Young Chung; Chul Woo Kim; Kyu-Won Kim

2001-01-01

120

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.

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

2013-01-01

121

Histone deacetylases: silencers for hire  

Microsoft Academic Search

Over the past few years, the long-standing idea that covalent modification of chromatin can play a role in determining states of gene activity has been confirmed. Eukaryotic genes can be silenced by deacetylation of acetyl-lysine moieties in the N-terminal tails of histones. Recent work links histone deacetylases with an increasing number of repressors, suggesting that deacetylation might be a rather

Huck Hui Ng; Adrian Bird

2000-01-01

122

SAP30, a novel protein conserved between human and yeast, is a component of a histone deacetylase complex.  

PubMed

Histone acetylation plays a key role in the regulation of eukaryotic gene expression. Recently, histone acetylation and deacetylation were found to be catalyzed by structurally distinct, multisubunit complexes that mediate, respectively, activation and repression of transcription. Here, we identify SAP30 as a novel component of the human histone deacetylase complex that includes Sin3, the histone deacetylases HDAC1 and HDAC2, histone binding proteins RbAp46 and RbAp48, as well as other polypeptides. Moreover, we describe a SAP30 homolog in yeast that is functionally related to Sin3 and the histone deacetylase Rpd3. The human SAP30 complex is active in deacetylating core histone octamers, but inactive in deacetylating nucleosomal histones due to the inability of the histone binding proteins RbAp46 and RbAp48 to gain access to nucleosomal histones. These results define SAP30 as a component of a histone deacetylase complex conserved among eukaryotic organisms. PMID:9651585

Zhang, Y; Sun, Z W; Iratni, R; Erdjument-Bromage, H; Tempst, P; Hampsey, M; Reinberg, D

1998-06-01

123

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

124

Histone deacetylase inhibitors reverse gene silencing in Friedreich's ataxia.  

PubMed

Expansion of GAA x TTC triplets within an intron in FXN (the gene encoding frataxin) leads to transcription silencing, forming the molecular basis for the neurodegenerative disease Friedreich's ataxia. Gene silencing at expanded FXN alleles is accompanied by hypoacetylation of histones H3 and H4 and trimethylation of histone H3 at Lys9, observations that are consistent with a heterochromatin-mediated repression mechanism. We describe the synthesis and characterization of a class of histone deacetylase (HDAC) inhibitors that reverse FXN silencing in primary lymphocytes from individuals with Friedreich's ataxia. We show that these molecules directly affect the histones associated with FXN, increasing acetylation at particular lysine residues on histones H3 and H4 (H3K14, H4K5 and H4K12). This class of HDAC inhibitors may yield therapeutics for Friedreich's ataxia. PMID:16921367

Herman, David; Jenssen, Kai; Burnett, Ryan; Soragni, Elisabetta; Perlman, Susan L; Gottesfeld, Joel M

2006-10-01

125

Detection of histone deacetylase inhibition by noninvasive magnetic resonance spectroscopy.  

PubMed

Histone deacetylase (HDAC) inhibitors are new and promising antineoplastic agents. Current methods for monitoring early response rely on invasive biopsies or indirect blood-derived markers. Our goal was to develop a magnetic resonance spectroscopy (MRS)-based method to detect HDAC inhibition. The fluorinated lysine derivative Boc-Lys-(Tfa)-OH (BLT) was investigated as a (19)F MRS molecular marker of HDAC activity together with (31)P MRS of endogenous metabolites. In silico modeling of the BLT-HDAC interaction and in vitro MRS studies of BLT cleavage by HDAC confirmed BLT as a HDAC substrate. BLT did not affect cell viability or HDAC activity in PC3 prostate cancer cells. PC3 cells were treated, in the presence of BLT, with the HDAC inhibitor p-fluoro-suberoylanilide hydroxamic acid (FSAHA) over the range of 0 to 10 micromol/L, and HDAC activity and MRS spectra were monitored. Following FSAHA treatment, HDAC activity dropped, reaching 53% of control at 10 micromol/L FSAHA. In parallel, a steady increase in intracellular BLT from 14 to 32 fmol/cell was observed. BLT levels negatively correlated with HDAC activity consistent with higher levels of uncleaved BLT in cells with inhibited HDAC. Phosphocholine, detected by (31)P MRS, increased from 7 to 16 fmol/cell following treatment with FSAHA and also negatively correlated with HDAC activity. Increased phosphocholine is probably due to heat shock protein 90 inhibition as indicated by depletion of client proteins. In summary, (19)F MRS of BLT, combined with (31)P MRS, can be used to monitor HDAC activity in cells. In principle, this could be applied in vivo to noninvasively monitor HDAC activity. PMID:16731766

Sankaranarayanapillai, Madhuri; Tong, William P; Maxwell, David S; Pal, Ashutosh; Pang, Jihai; Bornmann, William G; Gelovani, Juri G; Ronen, Sabrina M

2006-05-01

126

Histone Deacetylases and SAP18, a Novel Polypeptide, Are Components of a Human Sin3 Complex  

Microsoft Academic Search

An important event in gene expression is the covalent modification of histone proteins. We have found that the mammalian transcriptional repressor Sin3 (mSin3) exists in a complex with histone deacetylases HDAC1 and HDAC2. Consistent with the observation that mSin3-mediated repression of transcription involves the modification of histone polypeptides, we found that the mSin3-containing complex includes polypeptides that tether the mSin3

Yi Zhang; Rabah Iratni; Hediye Erdjument-Bromage; Paul Tempst; Danny Reinberg

1997-01-01

127

Histone Deacetylase Inhibitors Preserve Function in Aging Axons  

PubMed Central

Aging increases the vulnerability of aging white matter to ischemic injury. Histone deacetylase (HDAC) inhibitors preserve young adult white matter structure and function during ischemia by conserving ATP and reducing excitotoxicity. In isolated optic nerve from 12 month old mice, deprived of oxygen and glucose, we show that pan- and Class I specific HDAC inhibitors promote functional recovery of axons. This protection correlates with preservation of axonal mitochondria. The cellular expression of HDAC 3, in the central nervous system (CNS) and HDAC 2 in optic nerve considerably changed with age expanding to more cytoplasmic domains from nuclear compartments suggesting that changes in glial cell protein acetylation may confer protection to aging axons. Our results indicate manipulation of HDAC activities in glial cells may have a universal potential for stroke therapy across age groups.

Baltan, Selva

2012-01-01

128

Homo-oligomerisation and nuclear localisation of mouse histone deacetylase 1.  

PubMed

Reversible histone acetylation changes the chromatin structure and can modulate gene transcription. Mammalian histone deacetylase 1 (HDAC1) is a nuclear protein that belongs to a growing family of evolutionarily conserved enzymes catalysing the removal of acetyl residues from core histones and other proteins. Previously, we have identified murine HDAC1 as a growth factor-inducible protein in murine T-cells. Here, we characterise the molecular function of mouse HDAC1 in more detail. Co-immunoprecipitation experiments with epitope-tagged HDAC1 protein reveal the association with endogenous HDAC1 enzyme. We show that HDAC1 can homo-oligomerise and that this interaction is dependent on the N-terminal HDAC association domain of the protein. Furthermore, the same HDAC1 domain is also necessary for in vitro binding of HDAC2 and HDAC3, association with RbAp48 and for catalytic activity of the enzyme. A lysine-rich sequence within the carboxy terminus of HDAC1 is crucial for nuclear localisation of the enzyme. We identify a C-terminal nuclear localisation domain, which is sufficient for the transport of HDAC1 and of reporter fusion proteins into the nucleus. Alternatively, HDAC1 can be shuttled into the nucleus by association with another HDAC1 molecule via its N-terminal HDAC association domain. Our results define two domains, which are essential for the oligomerisation and nuclear localisation of mouse HDAC1. PMID:11302704

Taplick, J; Kurtev, V; Kroboth, K; Posch, M; Lechner, T; Seiser, C

2001-04-20

129

The functional interactome landscape of the human histone deacetylase family.  

PubMed

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

130

Interpreting clinical assays for histone deacetylase inhibitors  

PubMed Central

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

Martinet, Nadine; Bertrand, Philippe

2011-01-01

131

Functional Interaction between Class II Histone Deacetylases and ICP0 of Herpes Simplex Virus Type 1  

Microsoft Academic Search

This study describes the physical and functional interactions between ICP0 of herpes simplex virus type 1 and class II histone deacetylases (HDACs) 4, 5, and 7. Class II HDACs are mainly known for their partici- pation in the control of cell differentiation through the regulation of the activity of the transcription factor MEF2 (myocyte enhancer factor 2), implicated in muscle

Patrick Lomonte; Joelle Thomas; Pascale Texier; Cecile Caron; Saadi Khochbin; Alberto L. Epstein

2004-01-01

132

Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling  

Microsoft Academic Search

Angiogenesis is a complex biological process involving the coordinated modulation of many genes. Histone deacetylases (HDAC) are a growing family of enzymes that mediate the availability of chromatin to the transcriptional machinery. Trichostatin-A (TSA) and suberoylanilide hydroxamic acid (SAHA), two HDAC inhibitors known to relieve gene silencing, were evaluated as potential antiangiogenic agents. TSA and SAHA were shown to prevent

Christophe F Deroanne; Karine Bonjean; Sandrine Servotte; Laetitia Devy; Alain Colige; Nathalie Clausse; Sylvia Blacher; Eric Verdin; Jean-Michel Foidart; Betty V Nusgens; Vincent Castronovo

2002-01-01

133

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.

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

2013-01-01

134

Analysis of histone acetyltransferase and histone deacetylase families of Arabidopsis thaliana suggests functional diversification of chromatin modification among multicellular eukaryotes  

Microsoft Academic Search

Sequence similarity and profile searching tools were used to analyze the genome sequences of Arabidopsis thaliana, Saccharomyces cerevisiae, Schizosaccharomyces pombe, Caenorhabditis ele- gans and Drosophila melanogaster for genes encoding three families of histone deacetylase (HDAC) proteins and three families of histone acetyltransferase (HAT) proteins. Plants, animals and fungi were found to have a single member of each of three subfamilies

Ritu Pandey; Andreas Muller; Carolyn A. Napoli; David A. Selinger; Craig S. Pikaard; Eric J. Richards; Judith Bender; David W. Mount; Richard A. Jorgensen

2002-01-01

135

FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression  

PubMed Central

The forkhead family protein FOXP3 acts as a repressor of transcription and is both an essential and sufficient regulator of the development and function of regulatory T cells. The molecular mechanism by which FOXP3-mediated transcriptional repression occurs remains unclear. Here, we report that transcriptional repression by FOXP3 involves a histone acetyltransferase–deacetylase complex that includes histone acetyltransferase TIP60 (Tat-interactive protein, 60 kDa) and class II histone deacetylases HDAC7 and HDAC9. The N-terminal 106–190 aa of FOXP3 are required for TIP60–FOXP3, HDAC7–FOXP3 association, as well as for the transcriptional repression of FOXP3 via its forkhead domain. FOXP3 can be acetylated in primary human regulatory T cells, and TIP60 promotes FOXP3 acetylation in vivo. Overexpression of TIP60 but not its histone acetyltransferase-deficient mutant promotes, whereas knockdown of endogenous TIP60 relieved, FOXP3-mediated transcriptional repression. A minimum FOXP3 ensemble containing native TIP60 and HDAC7 is necessary for IL-2 production regulation in T cells. Moreover, FOXP3 association with HDAC9 is antagonized by T cell stimulation and can be restored by the protein deacetylation inhibitor trichostatin A, indicating a complex dynamic aspect of T suppressor cell regulation. These findings identify a previously uncharacterized complex-based mechanism by which FOXP3 actively mediates transcriptional repression.

Li, Bin; Samanta, Arabinda; Song, Xiaomin; Iacono, Kathryn T.; Bembas, Kathryn; Tao, Ran; Basu, Samik; Riley, James L.; Hancock, Wayne W.; Shen, Yuan; Saouaf, Sandra J.; Greene, Mark I.

2007-01-01

136

Histone deacetylase inhibitors: possible implications for neurodegenerative disorders.  

PubMed

During the past six years numerous studies identified histone deacetylase (HDAC) inhibitors as candidate drugs for the treatment of neurodegenerative disorders. Two major neuroprotective mechanisms of HDAC inhibitors have been identified, namely the transcriptional activation of disease-modifying genes and the correction of perturbations in histone acetylation homeostasis, which have been shown to be intimately involved in the neurodegenerative pathomechanisms of Huntington's, Parkinson's and Kennedy disease, amyotropic lateral sclerosis, Rubinstein-Taybi syndrome as well as stroke. Based on the promising in vitro and in vivo analyses, clinical trials have been initiated to evaluate the safety and efficacy of HDAC inhibitors for the treatment of devastating diseases such as Huntington's disease, amyotropic lateral sclerosis and spinal muscular atrophy. Here, the authors summarize and discuss the findings on the emerging field of epigenetic therapy strategies in neurodegenerative disorders. PMID:18230051

Hahnen, Eric; Hauke, Jan; Tränkle, Christian; Eyüpoglu, Ilker Y; Wirth, Brunhilde; Blümcke, Ingmar

2008-02-01

137

Histone deacetylases are critical targets of bortezomib-induced cytotoxicity in multiple myeloma.  

PubMed

Bortezomib is now widely used for the treatment of multiple myeloma (MM); however, its action mechanisms are not fully understood. Despite the initial results, recent investigations have indicated that bortezomib does not inactivate nuclear factor-kappaB activity in MM cells, suggesting the presence of other critical pathways leading to cytotoxicity. In this study, we show that histone deacetylases (HDACs) are critical targets of bortezomib, which specifically down-regulated the expression of class I HDACs (HDAC1, HDAC2, and HDAC3) in MM cell lines and primary MM cells at the transcriptional level, accompanied by reciprocal histone hyperacetylation. Transcriptional repression of HDACs was mediated by caspase-8-dependent degradation of Sp1 protein, the most potent transactivator of class I HDAC genes. Short-interfering RNA-mediated knockdown of HDAC1 enhanced bortezomib-induced apoptosis and histone hyperacetylation, whereas HDAC1 overexpression inhibited them. HDAC1 overexpression conferred resistance to bortezomib in MM cells, and administration of the HDAC inhibitor romidepsin restored sensitivity to bortezomib in HDAC1-overexpressing cells both in vitro and in vivo. These results suggest that bortezomib targets HDACs via distinct mechanisms from conventional HDAC inhibitors. Our findings provide a novel molecular basis and rationale for the use of bortezomib in MM treatment. PMID:20351311

Kikuchi, Jiro; Wada, Taeko; Shimizu, Rumi; Izumi, Tohru; Akutsu, Miyuki; Mitsunaga, Kanae; Noborio-Hatano, Kaoru; Nobuyoshi, Masaharu; Ozawa, Keiya; Kano, Yasuhiko; Furukawa, Yusuke

2010-07-22

138

Histone deacetylase activity regulates chemical diversity in Aspergillus.  

PubMed

Bioactive small molecules are critical in Aspergillus species during their development and interaction with other organisms. Genes dedicated to their production are encoded in clusters that can be located throughout the genome. We show that deletion of hdaA, encoding an Aspergillus nidulans histone deacetylase (HDAC), causes transcriptional activation of two telomere-proximal gene clusters--and subsequent increased levels of the corresponding molecules (toxin and antibiotic)--but not of a telomere-distal cluster. Introduction of two additional HDAC mutant alleles in a DeltahdaA background had minimal effects on expression of the two HdaA-regulated clusters. Treatment of other fungal genera with HDAC inhibitors resulted in overproduction of several metabolites, suggesting a conserved mechanism of HDAC repression of some secondary-metabolite gene clusters. Chromatin regulation of small-molecule gene clusters may enable filamentous fungi to successfully exploit environmental resources by modifying chemical diversity. PMID:17616629

Shwab, E Keats; Bok, Jin Woo; Tribus, Martin; Galehr, Johannes; Graessle, Stefan; Keller, Nancy P

2007-09-01

139

Novel Histone Deacetylase Inhibitors.  

National Technical Information Service (NTIS)

Advanced breast cancer is not curable by existing treatment regimens. The purpose of this project is to discover new drugs to treat breast cancer that act to restore the differentiated and non-growing state of breast tumor cells by inhibition of histone d...

J. S. Strobl

2004-01-01

140

Histone Deacetylase Inhibitors  

Microsoft Academic Search

The base sequence of DNA provides the genetic code for proteins. The regulation of expression or suppression of gene transcription is largely determined by the structure of the chromatin—referred to as epigenetic gene regulation (Agalioti et al., 2002; Jenuwein and Allis, 2001; Richards and Elgin, 2002; Spotswood and Turner, 2002; Zhang and Reinberg, 2001). Posttranslational modifications of the histones of

Paul A. Marks; Victoria M. Richon; Thomas Miller; William Kevin Kelly

2004-01-01

141

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

142

Identification of a series of substituted 2-piperazinyl-5-pyrimidylhydroxamic acids as potent histone deacetylase inhibitors.  

PubMed

Pursuing our efforts in designing 5-pyrimidylhydroxamic acid anti-cancer agents, we have identified a new series of potent histone deacetylase (HDAC) inhibitors. These compounds exhibit enzymatic HDAC inhibiting properties with IC(50) values in the nanomolar range and inhibit tumor cell proliferation at similar levels. Good solubility, moderate bioavailability, and promising in vivo activity in xenograft model made this series of compounds interesting starting points to design new potent HDAC inhibitors. PMID:19906529

Angibaud, Patrick; Van Emelen, Kristof; Decrane, Laurence; van Brandt, Sven; Ten Holte, Peter; Pilatte, Isabelle; Roux, Bruno; Poncelet, Virginie; Speybrouck, David; Queguiner, Laurence; Gaurrand, Sandrine; Mariën, Ann; Floren, Wim; Janssen, Lut; Verdonck, Marc; van Dun, Jacky; van Gompel, Jacky; Gilissen, Ron; Mackie, Claire; Du Jardin, Marc; Peeters, Jozef; Noppe, Marc; Van Hijfte, Luc; Freyne, Eddy; Page, Martin; Janicot, Michel; Arts, Janine

2010-01-01

143

The epigenetic regulator Histone Deacetylase 1 promotes transcription of a core neurogenic programme in zebrafish embryos  

Microsoft Academic Search

BACKGROUND: The epigenetic regulator Histone Deacetylase 1 (Hdac1) is required for specification and patterning of neurones and myelinating glia during development of the vertebrate central nervous system (CNS). This co-ordinating function for Hdac1 is evolutionarily conserved in zebrafish and mouse, but the mechanism of action of Hdac1 in the developing CNS is not well-understood. RESULTS: A genome-wide comparative analysis of

Michael RM Harrison; Aristophanes S Georgiou; Herman P Spaink; Vincent T Cunliffe

2011-01-01

144

Class II Histone Deacetylases Act as Signal-Responsive Repressors of Cardiac Hypertrophy  

Microsoft Academic Search

The heart responds to stress signals by hypertrophic growth, which is accompanied by activation of the MEF2 transcription factor and reprogramming of cardiac gene expression. We show here that class II histone deacetylases (HDACs), which repress MEF2 activity, are substrates for a stress-responsive kinase specific for conserved serines that regulate MEF2-HDAC interactions. Signal-resistant HDAC mutants lacking these phosphorylation sites are

Chun Li Zhang; Timothy A. McKinsey; Shurong Chang; Christopher L. Antos; Joseph A. Hill; Eric N. Olson

2002-01-01

145

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.

Khabele, Dineo

2014-01-01

146

Induction of human ? globin gene expression by histone deacetylase inhibitors  

PubMed Central

We investigated the induction of human ? globin gene activity by 3 classes of histone deacetylase inhibitors: amide analogues of trichostatin A, hydroxamic acid analogues of trapoxin, and scriptaid and its analogues. The screening consisted of measuring the effects of these compounds on ? and ? human gene promoter activity by using cultures of GM979 cells stably transfected with a construct containing a ? promoter linked to firefly luciferase and a ? promoter linked to renilla luciferase. Compounds belonging to all 3 classes induced ? gene promoter activity in the screening assay in low micromolar concentrations. Histone deacetylase (HDAC) inhibitors increased acetylation of histone H4 and induced the expression of endogenous murine embryonic genes. They also increased the levels of ? mRNA and the frequency of fetal hemoglobin-containing erythroblasts in erythroid burst-forming unit (BFUe) cultures from healthy adult individuals. Compounds that displayed very similar degrees of inhibition of the HDAC activity in an HDAC enzymatic assay differed strikingly on their effects on ? gene promoter activity, raising the possibility of selectivity of HDACs that interact with the ? globin gene chromatin.

Cao, Hua; Stamatoyannopoulos, George; Jung, Manfred

2010-01-01

147

Histone deacetylase 1 phosphorylation at S421 and S423 is constitutive in vivo, but dispensable in vitro  

Microsoft Academic Search

Histone Deacetylase 1 (HDAC1) is a transcriptional regulator associated with proliferation, apoptosis, and tumorigenesis, although its precise cellular role is unclear. HDAC1 was previously characterized as a phosphoprotein where mutation of phosphorylated S421 and S423 resulted in a loss of deacetylase activity and protein association. Here, the role of phosphorylation in regulating HDAC1 function was examined using phospho-specific antibodies. The

Paulina Karwowska-Desaulniers; Anastasia Ketko; Nayana Kamath; Mary Kay H.. Pflum

2007-01-01

148

Histone deacetylase regulation of ATM-mediated DNA damage signaling.  

PubMed

Ataxia-telangiectasia mutated (ATM) is a major regulator of the DNA damage response. ATM promotes the activation of BRCA1, CHK2, and p53 leading to the induction of response genes such as CDKN1A (p21), GADD45A, and RRM2B that promote cell-cycle arrest and DNA repair. The upregulation of these response genes may contribute to resistance of cancer cells to genotoxic therapies. Here, we show that histone deacetylases (HDAC) play a major role in mitigating the response of the ATM pathway to DNA damage. HDAC inhibition decreased ATM activation and expression, and attenuated the activation of p53 in vitro and in vivo. Select depletion of HDAC1 and HDAC2 was sufficient to modulate ATM activation, reduce GADD45A and RRM2B induction, and increase sensitivity to DNA strand breaks. The regulation of ATM by HDAC enzymes therefore suggests a vital role for HDAC1 and HDAC2 in the DNA damage response, and the potential use of the ATM pathway as a pharmacodynamic marker for combination therapies involving HDAC inhibitors. PMID:23939379

Thurn, K Ted; Thomas, Scott; Raha, Paromita; Qureshi, Ian; Munster, Pamela N

2013-10-01

149

Histone deacetylase 10 promotes autophagy-mediated cell survival  

PubMed Central

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

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

2013-01-01

150

Metabolism as a key to histone deacetylase inhibition  

PubMed Central

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

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

2012-01-01

151

Metabolism as a key to histone deacetylase inhibition.  

PubMed

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

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

2011-06-01

152

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

153

Developing histone deacetylase inhibitors in the therapeutic armamentarium of pancreatic adenocarcinoma.  

PubMed

Introduction: Histone deacetylases (HDACs) are commonly dysregulated in pancreatic adenocarcinoma (PA) and have a central role in the development and progression of the disease. HDAC is a family of enzymes involved in deacetylation of lysine residues on histone and non-histone proteins. Deacetylation of histone proteins leads to compaction of the DNA/histone complex resulting in inhibition of gene expression. Deacetylation of non-histone proteins can affect the stability and function of key proteins leading to dysregulation of cellular signaling pathways. HDAC inhibitors have been shown to potentiate the antiproliferative and proapoptotic effects of several cytotoxic agents, in vitro and in vivo PA xenograft models. Areas covered: The areas covered include the biology and function of the HDAC isoenzymes and their significant role in multiple oncogenic pathways in PA. Preclinical and clinical trials evaluating HDAC inhibitors are also reviewed. Expert opinion: Despite discouraging early phase clinical trials evaluating HDAC inhibitors in PA, this strategy deserves further evaluation guided by better preclinical studies in identifying the role of specific HDAC isoenzyme inhibitors in PA. Evaluation of the effects of HDAC inhibitors on PA stem cell function and epithelial to mesenchymal transformation is also an evolving area that holds future potential for these agents. Such preclinical studies will yield insight into the functionality of HDAC isoenzymes, which can then be translated into rationally designed clinical trials. One such strategy could focus on HDAC inhibition employed in combination with proteasome inhibition targeting the aggresome pathway in PA. PMID:22621256

Zafar, Syed F; Nagaraju, Ganji Purnachandra; El-Rayes, Bassel

2012-07-01

154

Nuclear receptor corepressor and histone deacetylase 3 govern circadian metabolic physiology  

Microsoft Academic Search

Rhythmic changes in histone acetylation at circadian clock genes suggest that temporal modulation of gene expression is regulated by chromatin modifications. Furthermore, recent studies demonstrate a critical relationship between circadian and metabolic physiology. The nuclear receptor corepressor 1 (Ncor1) functions as an activating subunit for the chromatin modifying enzyme histone deacetylase 3 (Hdac3). Lack of Ncor1 is incompatible with life,

Theresa Alenghat; Katherine Meyers; Shannon E. Mullican; Kirstin Leitner; Adetoun Adeniji-Adele; Jacqueline Avila; Maja Bucan; Rexford S. Ahima; Klaus H. Kaestner; Mitchell A. Lazar

2008-01-01

155

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

PubMed

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

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

2012-11-01

156

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.

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

2012-01-01

157

Histone deacetylases 1 and 2 maintain S-phase chromatin and DNA replication fork progression  

PubMed Central

Background Histone deacetylases (HDACs) play a critical role in the maintenance of genome stability. Class I HDACs, histone deacetylase 1 and 2 (Hdac1 and Hdac2) are recruited to the replication fork by virtue of their interactions with the replication machinery. However, functions for Hdac1 and Hdac2 (Hdacs1,2) in DNA replication are not fully understood. Results Using genetic knockdown systems and novel Hdacs1,2-selective inhibitors, we found that loss of Hdacs1,2 leads to a reduction in the replication fork velocity, and an increase in replication stress response culminating in DNA damage. These observed defects are due to a direct role for Hdacs1,2 in DNA replication, as transcription of genes involved in replication was not affected in the absence of Hdacs1,2. We found that loss of Hdacs1,2 functions increases histone acetylation (ac) on chromatin in S-phase cells and affects nascent chromatin structure, as evidenced by the altered sensitivity of newly synthesized DNA to nuclease digestion. Specifically, H4K16ac, a histone modification involved in chromatin decompaction, is increased on nascent chromatin upon abolishing Hdacs1,2 activities. It was previously shown that H4K16ac interferes with the functions of SMARCA5, an ATP-dependent ISWI family chromatin remodeler. We found SMARCA5 also associates with nascent DNA and loss of SMARCA5 decreases replication fork velocity similar to the loss or inhibition of Hdacs1,2. Conclusions Our studies reveal important roles for Hdacs1,2 in nascent chromatin structure maintenance and regulation of SMARCA5 chromatin-remodeler function, which together are required for proper replication fork progression and genome stability in S-phase.

2013-01-01

158

Troglitazone inhibits histone deacetylase activity in breast cancer cells.  

PubMed

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

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

2010-02-28

159

Histone Deacetylase 1 Can Repress Transcription by Binding to Sp1  

Microsoft Academic Search

The members of the Sp1 transcription factor family can act as both negative and positive regulators of gene expression. Here we show that Sp1 can be a target for histone deacetylase 1 (HDAC1)-mediated transcriptional repression. The histone deacetylase inhibitor trichostatin A activates the chromosomally integrated murine thymidine kinase promoter in an Sp1-dependent manner. Coimmunoprecipitation experiments with Swiss 3T3 fibroblasts and

ANGELIKA DOETZLHOFER; HANS ROTHENEDER; GERDA LAGGER; MANFRED KORANDA; VLADISLAV KURTEV; GERALD BROSCH; ERHARD WINTERSBERGER; CHRISTIAN SEISER

1999-01-01

160

Disruption of I?B Kinase (IKK)-mediated RelA Serine 536 Phosphorylation Sensitizes Human Multiple Myeloma Cells to Histone Deacetylase (HDAC) Inhibitors*  

PubMed Central

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

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

2011-01-01

161

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.

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

162

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.

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

163

Histone deacetylase expression patterns in developing murine optic nerve  

PubMed Central

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

2014-01-01

164

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

165

Antimalarial Activity of the Anticancer Histone Deacetylase Inhibitor SB939  

PubMed Central

Histone deacetylase (HDAC) enzymes posttranslationally modify lysines on histone and nonhistone proteins and play crucial roles in epigenetic regulation and other important cellular processes. HDAC inhibitors (e.g., suberoylanilide hydroxamic acid [SAHA; also known as vorinostat]) are used clinically to treat some cancers and are under investigation for use against many other diseases. Development of new HDAC inhibitors for noncancer indications has the potential to be accelerated by piggybacking onto cancer studies, as several HDAC inhibitors have undergone or are undergoing clinical trials. One such compound, SB939, is a new orally active hydroxamate-based HDAC inhibitor with an improved pharmacokinetic profile compared to that of SAHA. In this study, the in vitro and in vivo antiplasmodial activities of SB939 were investigated. SB939 was found to be a potent inhibitor of the growth of Plasmodium falciparum asexual-stage parasites in vitro (50% inhibitory concentration [IC50], 100 to 200 nM), causing hyperacetylation of parasite histone and nonhistone proteins. In combination with the aspartic protease inhibitor lopinavir, SB939 displayed additive activity. SB939 also potently inhibited the in vitro growth of exoerythrocytic-stage Plasmodium parasites in liver cells (IC50, ?150 nM), suggesting that inhibitor targeting to multiple malaria parasite life cycle stages may be possible. In an experimental in vivo murine model of cerebral malaria, orally administered SB939 significantly inhibited P. berghei ANKA parasite growth, preventing development of cerebral malaria-like symptoms. These results identify SB939 as a potent new antimalarial HDAC inhibitor and underscore the potential of investigating next-generation anticancer HDAC inhibitors as prospective new drug leads for treatment of malaria.

Sumanadasa, Subathdrage D. M.; Goodman, Christopher D.; Lucke, Andrew J.; Skinner-Adams, Tina; Sahama, Ishani; Haque, Ashraful; Do, Tram Anh; McFadden, Geoffrey I.; Fairlie, David P.

2012-01-01

166

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.

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

2013-01-01

167

RbAp48 belongs to the histone deacetylase complex that associates with the retinoblastoma protein.  

PubMed

The retinoblastoma susceptibility gene product, the Rb protein, is a key regulator of mammalian cell proliferation. One of the major targets of Rb is the S phase inducing E2F transcription factor. Once bound to E2F, Rb represses the expression of E2F-regulated genes. Transcriptional repression by Rb is believed to be crucial for the proper control of cell growth. Recently, we and others showed that Rb represses transcription through the recruitment of a histone deacetylase. Interestingly, we show here that the Rb-associated histone deacetylase complex could deacetylate polynucleosomal substrates, indicating that other proteins could be present within this complex. The Rb-associated protein RbAp48 belongs to many histone deacetylase complexes. We show here that the histone deacetylase HDAC1 is able to mediate the formation of a ternary complex containing Rb and RbAp48. Moreover, less deacetylase activity was found associated with Rb in cell extracts depleted for RbAp48 containing complexes, demonstrating that Rb, histone deacetylase, and RbAp48 are physically associated in live cells. Taken together, these data indicate that RbAp48 is a component of the histone deacetylase complex recruited by Rb. Finally, we found that E2F1 and RbAp48 are physically associated in the presence of Rb and HDAC1, suggesting that RbAp48 could be involved in transcriptional repression of E2F-responsive genes. PMID:10734134

Nicolas, E; Morales, V; Magnaghi-Jaulin, L; Harel-Bellan, A; Richard-Foy, H; Trouche, D

2000-03-31

168

Homo-oligomerisation and nuclear localisation of mouse histone deacetylase 1 1 1 Edited by J. Karn  

Microsoft Academic Search

Reversible histone acetylation changes the chromatin structure and can modulate gene transcription. Mammalian histone deacetylase 1 (HDAC1) is a nuclear protein that belongs to a growing family of evolutionarily conserved enzymes catalysing the removal of acetyl residues from core histones and other proteins. Previously, we have identified murine HDAC1 as a growth factor-inducible protein in murine T-cells. Here, we characterise

Jan Taplick; Vladislav Kurtev; Karin Kroboth; Markus Posch; Thomas Lechner; Christian Seiser

2001-01-01

169

Reactivation of latent HIV by histone deacetylase inhibitors  

PubMed Central

Latent HIV persists in CD4+ T cells in infected patients under antiretroviral therapy (ART). Latency is associated with transcriptional silencing of the integrated provirus and driven, at least in part, by histone deacetylases (HDACs), a family of chromatin associated proteins that regulate histone acetylation and the accessibility of DNA to transcription factors. Remarkably, inhibition of HDACs is sufficient to reactivate a fraction of latent HIV in a variety of experimental systems. This basic observation led to the shock and kill idea that forcing the transcriptional activation of HIV might lead to virus expression, to virus-or host-induced cell death of the reactivated cells, and to the eradication of the pool of latently infected cells. Such intervention might possibly lead to a cure for HIV infected patients. Here, we review the basic biology of HDACs and their inhibitors, the role of HDACs in HIV latency and recent efforts to use HDAC inhibitors to reactivate latent HIV in vitro and in vivo.

Shirakawa, Kotaro; Chavez, Leonard; Hakre, Shweta; Calvanese, Vincenzo; Verdin, Eric

2013-01-01

170

Reactivation of latent HIV by histone deacetylase inhibitors.  

PubMed

Latent HIV persists in CD4(+) T cells in infected patients under antiretroviral therapy (ART). Latency is associated with transcriptional silencing of the integrated provirus and driven, at least in part, by histone deacetylases (HDACs), a family of chromatin-associated proteins that regulate histone acetylation and the accessibility of DNA to transcription factors. Remarkably, inhibition of HDACs is sufficient to reactivate a fraction of latent HIV in a variety of experimental systems. This basic observation led to the shock and kill idea that forcing the transcriptional activation of HIV might lead to virus expression, to virus- or host-induced cell death of the reactivated cells, and to the eradication of the pool of latently infected cells. Such intervention might possibly lead to a cure for HIV-infected patients. Here, we review the basic biology of HDACs and their inhibitors, the role of HDACs in HIV latency, and recent efforts to use HDAC inhibitors to reactivate latent HIV in vitro and in vivo. PMID:23517573

Shirakawa, Kotaro; Chavez, Leonard; Hakre, Shweta; Calvanese, Vincenzo; Verdin, Eric

2013-06-01

171

Requirement of a novel splicing variant of human histone deacetylase 6 for TGF-{beta}1-mediated gene activation  

SciTech Connect

Histone deacetylase 6 (HDAC6) belongs to the family of class IIb HDACs and predominantly deacetylates non-histone proteins in the cytoplasm via the C-terminal deacetylase domain of its two tandem deacetylase domains. HDAC6 modulates fundamental cellular processes via deacetylation of {alpha}-tubulin, cortactin, molecular chaperones, and other peptides. Our previous study indicates that HDAC6 mediates TGF-{beta}1-induced epithelial-mesenchymal transition (EMT) in A549 cells. In the current study, we identify a novel splicing variant of human HDAC6, hHDAC6p114. The hHDAC6p114 mRNA arises from incomplete splicing and encodes a truncated isoform of the hHDAC6p114 protein of 114 kDa when compared to the major isoform hHDAC6p131. The hHDAC6p114 protein lacks the first 152 amino acids from N-terminus in the hHDAC6p131 protein, which harbors a nuclear export signal peptide and 76 amino acids of the N-terminal deacetylase domain. hHDAC6p114 is intact in its deacetylase activity against {alpha}-tubulin. The expression hHDAC6p114 is elevated in a MCF-7 derivative that exhibits an EMT-like phenotype. Moreover, hHDAC6p114 is required for TGF-{beta}1-activated gene expression associated with EMT in A549 cells. Taken together, our results implicate that expression and function of hHDAC6p114 is differentially regulated when compared to hHDAC6p131.

Zhuang, Yan [Department of Medicine, Tulane School of Medicine, New Orleans, LA 70112 (United States)] [Department of Medicine, Tulane School of Medicine, New Orleans, LA 70112 (United States); Nguyen, Hong T. [Graduate Program in Biomedical Sciences, Tulane School of Medicine, New Orleans, LA 70112 (United States)] [Graduate Program in Biomedical Sciences, Tulane School of Medicine, New Orleans, LA 70112 (United States); Lasky, Joseph A. [Department of Medicine, Tulane School of Medicine, New Orleans, LA 70112 (United States)] [Department of Medicine, Tulane School of Medicine, New Orleans, LA 70112 (United States); Cao, Subing [Graduate Program in Biomedical Sciences, Tulane School of Medicine, New Orleans, LA 70112 (United States)] [Graduate Program in Biomedical Sciences, Tulane School of Medicine, New Orleans, LA 70112 (United States); Li, Cui [Department of Medicine, Tulane School of Medicine, New Orleans, LA 70112 (United States) [Department of Medicine, Tulane School of Medicine, New Orleans, LA 70112 (United States); Xiangya Hospital, Central South University, Hunan 41008 (China); Hu, Jiyao; Guo, Xinyue; Burow, Matthew E. [Department of Medicine, Tulane School of Medicine, New Orleans, LA 70112 (United States)] [Department of Medicine, Tulane School of Medicine, New Orleans, LA 70112 (United States); Shan, Bin, E-mail: bshan@tulane.edu [Department of Medicine, Tulane School of Medicine, New Orleans, LA 70112 (United States)] [Department of Medicine, Tulane School of Medicine, New Orleans, LA 70112 (United States)

2010-02-19

172

Histone deacetylase inhibitors enhance phosphorylation of histone H2AX after ionizing radiation  

SciTech Connect

Purpose Histone deacetylase (HDAC) inhibitors are believed to be promising radiosensitizers. To explore their effects on ionizing radiation (IR), we examined whether the HDAC inhibitors m-carboxycinnamic acid bis-hydroxamide (CBHA) and depsipeptide FK228 affect H2AX phosphorylation ({gamma}-H2AX), a landmark of DNA double-strand breaks after IR exposure. Methods and Materials We evaluated the effects of the HDAC inhibitors on clonogenic assay in human lung carcinoma A549 cells and progression of A549 xenograft tumors. IR-induced DNA damage was evaluated by histone {gamma}-H2AX. Histone hyperacetylation was induced by overexpression of histone acetyltransferase p300 and evaluated by Western blots. Results M-carboxycinnamic acid bishydroxyamide pretreatment radiosensitized A549 cells and strongly inhibited A549 xenograft tumor progression. CBHA and FK228, but not 5-fluorouracil, enhanced IR-induced {gamma}-H2AX in A549 and other cancer cell lines. Overexpression of p300 similarly augmented IR-induced {gamma}-H2AX. Conclusion The results of this study suggest that HDAC inhibitors enhance IR-induced {gamma}-H2AX, most likely through histone hyperacetylation, and radiosensitize various cancers.

Zhang Yubin [Division of Molecular Oncology and Molecular Diagnosis, Graduate School of Medicine, Sapporo Medical University, Sapporo, Hokkaido (Japan); Adachi, Masaaki [Division of Molecular Oncology and Molecular Diagnosis, Graduate School of Medicine, Sapporo Medical University, Sapporo, Hokkaido (Japan) and First Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Hokkaido (Japan)]. E-mail: adachi@sapmed.ac.jp; Zou Huichao [Division of Molecular Oncology and Molecular Diagnosis, Graduate School of Medicine, Sapporo Medical University, Sapporo, Hokkaido (Japan); Department of Radiology, Sapporo Medical University School of Medicine, Sapporo, Hokkaido (Japan); Hareyama, Masato [Department of Radiology, Sapporo Medical University School of Medicine, Sapporo, Hokkaido (Japan); Imai, Kohzoh [First Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Hokkaido (Japan); Shinomura, Yasuhisa [First Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Hokkaido (Japan)

2006-07-01

173

Characterization of the Regulation and Function of Zinc-Dependent Histone Deacetylases During Mouse Liver Regeneration  

PubMed Central

The studies reported here were undertaken to define the regulation and functional importance of zinc-dependent histone deacetylase (Zn-HDAC) activity during liver regeneration using the mouse partial hepatectomy (PH) model. The results showed that hepatic HDAC activity was significantly increased in nuclear and cytoplasmic fractions following PH. Further analyses showed isoform-specific effects of PH on HDAC mRNA and protein expression, with increased expression of the class I HDACs, 1 and 8, and class II HDAC4 in regenerating liver. Hepatic expression of (class II) HDAC5 was unchanged after PH; however HDAC5 exhibited transient nuclear accumulation in regenerating liver. These changes in hepatic HDAC expression, subcellular localization, and activity coincided with diminished histone acetylation in regenerating liver. The significance of these events was investigated by determining the effects of suberoylanilide hydroxyamic acid (SAHA, a specific inhibitor of Zn-HDAC activity) on hepatic regeneration. The results showed that SAHA-treatment suppressed the effects of PH on histone deacetylation and hepatocellular BrdU incorporation. Further examination showed that SAHA blunted hepatic expression and activation of cell cycle signals downstream of induction of cyclin D1 expression in mice subjected to PH. Conclusion The data reported here demonstrate isoform-specific regulation of Zn-HDAC expression, subcellular localization, and activity in regenerating liver. These studies also indicate that HDAC activity promotes liver regeneration by regulating hepatocellular cell cycle progression at a step downstream of cyclin D1 induction.

Huang, Jiansheng; Barr, Emily; Rudnick, David A.

2013-01-01

174

Characterization of the regulation and function of zinc-dependent histone deacetylases during rodent liver regeneration.  

PubMed

The studies reported here were undertaken to define the regulation and functional importance of zinc-dependent histone deacetylase (Zn-HDAC) activity during liver regeneration using the mouse partial hepatectomy (PH) model. The results showed that hepatic HDAC activity was significantly increased in nuclear and cytoplasmic fractions following PH. Further analyses showed isoform-specific effects of PH on HDAC messenger RNA (mRNA) and protein expression, with increased expression of the class I HDACs, 1 and 8, and class II HDAC4 in regenerating liver. Hepatic expression of (class II) HDAC5 was unchanged after PH; however, HDAC5 exhibited transient nuclear accumulation in regenerating liver. These changes in hepatic HDAC expression, subcellular localization, and activity coincided with diminished histone acetylation in regenerating liver. The significance of these events was investigated by determining the effects of suberoylanilide hydroxyamic acid (SAHA, a specific inhibitor of Zn-HDAC activity) on hepatic regeneration. The results showed that SAHA treatment suppressed the effects of PH on histone deacetylation and hepatocellular bromodeoxyuridine (BrdU) incorporation. Further examination showed that SAHA blunted hepatic expression and activation of cell cycle signals downstream of induction of cyclin D1 expression in mice subjected to PH. Conclusion: The data reported here demonstrate isoform-specific regulation of Zn-HDAC expression, subcellular localization, and activity in regenerating liver. These studies also indicate that HDAC activity promotes liver regeneration by regulating hepatocellular cell cycle progression at a step downstream of cyclin D1 induction. PMID:23258575

Huang, Jiansheng; Barr, Emily; Rudnick, David A

2013-05-01

175

Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB:CBP-dependent transcriptional activation.  

PubMed

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

2007-06-01

176

Inhibitors of histone deacetylase as new anticancer agents.  

PubMed

Inhibitors of histone deacetylase (HDAC) are an emerging class of anticancer agents. They induce hyperacetylation in chromatin usually resulting in activation of certain genes. They induce terminal cell differentiation and/or apoptosis in cancer cells. Histone deacetylase activity is recruited by co-repressor proteins to certain regions of the chromatin and aberrant histone acetylation caused by that recruitment is responsible for the pathogenesis of certain cancers on a molecular level. Inhibitors of HDAC have been identified in natural sources and also synthetic inhibitors are available. The best studied inhibitor is trichostatin A, a hydroxamic acid that exerts its activity by complexation of a zinc ion that is supposed to mediate the acetamide cleavage at the catalytic site. There are several synthetic hydroxamic acids that bear resemblance to trichostatin. Another class of potent inhibitors are naturally occurring and synthetic cyclotetrapeptides that all contain an unusual amino acid with an epoxyketone, ketone or hydroxamic acid function in the side chain. Phenylacetate, phenylbutyrate, butyrate and similar short chain fatty acids are also weak inhibitors. Further inhibitors from natural sources are the epoxide depudecin and depsipeptide FR 901228. The benzamide MS-275 belongs to a new class of synthetic HDAC inhibitors and displays oral activity in animal models. First clinical studies have shown that histone hyperacetylation can be achieved safely in humans and that treatment of cancer is possible. Thus, inhibitors of HDAC are one of the most promising class of new anticancer agents. New screening assays are useful tools that will facilitate identification of further inhibitors. PMID:11562279

Jung, M

2001-10-01

177

Rational therapeutic combinations with histone deacetylase inhibitors for the treatment of cancer  

PubMed Central

Histone deacetylases (HDACs) regulate the acetylation of a variety of histone and nonhistone proteins, controlling the transcription and regulation of genes involved in cell cycle control, proliferation, survival, DNA repair and differentiation. Unsurprisingly, HDAC expression is frequently altered in hematologic and solid tumor malignancies. Two HDAC inhibitors (vorinostat and romidepsin) have been approved by the US FDA for the treatment of cutaneous T-cell lymphoma. As single agents, treatment with HDAC inhibitors has demonstrated limited clinical benefit for patients with solid tumors, prompting the investigation of novel treatment combinations with other cancer therapeutics. In this article, the rationales and clinical progress of several combinations with HDAC inhibitors are presented, including DNA-damaging chemotherapeutic agents, radiotherapy, hormonal therapies, DNA methyltransferase inhibitors and various small-molecule inhibitors. The future application of HDAC inhibitors as a treatment for cancer is discussed, examining current hurdles to overcome before realizing the potential of this new approach.

Thurn, K Ted; Thomas, Scott; Moore, Amy; Munster, Pamela N

2011-01-01

178

New sulfurated derivatives of valproic acid with enhanced histone deacetylase inhibitory activity.  

PubMed

One dithiolthione and two new methanethiosulfonate derivatives of valproic acid (VPA) were synthesized and tested in vitro as histone deacetylase (HDAC) inhibitors. The new molecules, as well as their sulfurated moieties, exhibited a much stronger inhibition of HDAC enzymatic and antiproliferative activities and histone hyperacetylation than VPA. ACS 2 is the most interesting compound among the new VPA derivatives and its sulfurated moiety, 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione, also known to be a metabolite of anethole trithione, seems to contribute significantly to its activity. This is the first time that HDAC inhibitory activity is described for dithiolethiones and thiosulfonates. PMID:18294844

Perrino, Elena; Cappelletti, Graziella; Tazzari, Valerio; Giavini, Erminio; Del Soldato, Piero; Sparatore, Anna

2008-03-15

179

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

PubMed

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

Emanuele, Sonia; Lauricella, Marianna; Tesoriere, Giovanni

2008-10-01

180

Histone deacetylase inhibitors in cancer therapy.  

PubMed

Histone deacetylase inhibitors (HDAC inhibitors) represent a novel class of antineoplastic agents that act by promoting acetylation of histones, leading in turn to uncoiling of chromatin and activation of a variety of genes implicated in the regulation of cell surivival, proliferation, differentiation, and apoptosis. The major classes of HDIs include shortchain fatty acids, hydroxamic acid derivatives, synthetic benzamide derivatives, and cyclic tetrapeptides. Members of each of these classes have now entered clinical trials in humans. Despite their shared capacity to trigger histone deacetylation, individual HDIs exert diverse actions on cell cycle regulatory, signal transduction, and survival-related proteins which in all probability accounts for their disparate actions. Major areas of investigation surrounding HDIs include elucidating the mechanisms by which they induce apoptosis in neoplastic cells, and characterizing the factors responsible for the decision of such cells to undergo maturation versus cell death in the response to these agents. In this context, attention has recently focused on the ability of HDIs to induce perturbations in cell cycle regulatory proteins (e.g., p21(CIP1)), downregulation of survival signaling pathways (e.g., Raf/MEK/ERK), and disruption of cellular redox state (e.g., induction of reactive oxygen species; ROS). Aside from efforts to combine HDIs with established cytotoxic drugs, attempts are underway to establish a rational basis for combining HDIs with differentiation- inducing agents (e.g., ATRA, hypomethylating agents such as 5'-deoxyazacytine) with the goal of triggering re-expression of turn or suppressor and/or differentiation-associated genes. Finally, the results of recent preclinical studies provide a strong rationale for combining HDIs with other novel, molecularly targeted agents, including inhibitors of survival signaling pathways or cell cycle progression. Collectively, these findings should provide a fertile environment for the development of novel HDI-containing regimens in the treatment of cancer for many years to come. PMID:12673114

Rosato, Roberto R; Grant, Steven

2003-01-01

181

Screening of selective histone deacetylase inhibitors by proteochemometric modeling  

PubMed Central

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

2012-01-01

182

Design and Synthesis of Novel Hybrid Benzamide-Peptide Histone Deacetylase Inhibitors  

PubMed Central

We designed and synthesized a series of novel hybrid histone deacetylase inhibitors based on conjugation of benzamide-type inhibitors with either linear or cyclic peptides. Linear tetrapeptides (compounds 13 and 14), cyclic tetrapeptides (compounds 1 and 11), and heptanediamide-peptide conjugates (compounds 10, 12, 15 and 16) were synthesized through on-resin solid-phase peptide synthesis (SPPS). All compounds were found to be moderate HDAC1 and HDAC3 inhibitors, with IC50 values ranging from 1.3 µM to 532 µM. Interestingly, compound 15 showed 19-fold selectivity for HDAC3 versus HDAC1.

Hu, Fang; Chou, C. James

2011-01-01

183

Preclinical data and early clinical experience supporting the use of histone deacetylase inhibitors in multiple myeloma.  

PubMed

Histone deacetylases (HDACs) mediate protein acetylation states, which in turn regulate normal cellular processes often dysregulated in cancer. These observations led to the development of HDAC inhibitors that target tumors through multiple effects on protein acetylation. Clinical evidence demonstrates that treatment with HDAC inhibitors (such as vorinostat, panobinostat, and romidepsin) in combination with other antimyeloma agents (such as proteasome inhibitors and immunomodulatory drugs) has promising antitumor activity in relapsed/refractory multiple myeloma patients. This mini-review highlights the role of protein acetylation in the development of cancers and the rationale for the use of HDAC inhibitors in this patient population. PMID:23582718

Richardson, Paul G; Mitsiades, Constantine S; Laubach, Jacob P; Hajek, Roman; Spicka, Ivan; Dimopoulos, Meletios A; Moreau, Philippe; Siegel, David S; Jagannath, Sundar; Anderson, Kenneth C

2013-07-01

184

Histone Deacetylases Associated with the mSin3 Corepressor Mediate Mad Transcriptional Repression  

Microsoft Academic Search

Transcriptional repression by Mad–Max heterodimers requires interaction of Mad with the corepressors mSin3A\\/B. Sin3p, the S. cerevisiae homolog of mSin3, functions in the same pathway as Rpd3p, a protein related to two recently identified mammalian histone deacetylases, HDAC1 and HDAC2. Here, we demonstrate that mSin3A and HDAC1\\/2 are associated in vivo. HDAC2 binding requires a conserved region of mSin3A capable

Carol D. Laherty; Wen-Ming Yang; Jian-Min Sun; James R. Davie; Edward Seto; Robert N. Eisenman

1997-01-01

185

HDAC Inhibitors  

Microsoft Academic Search

Natural and synthetic inhibitors of histone deacetylases (HDACs) have not only contributed to the discovery of HDAC enzyme\\u000a molecules and the elucidation of their functions but have also developed as attractive therapeutic agents for diseases including\\u000a cancer. After the disclosure of the crystal structure of the HDAC-like protein bound to the inhibitor, the momentum of research\\u000a on HDAC inhibitors increased,

Akihiro Ito; Norikazu Nishino; Minoru Yoshida

186

Histone deacetylase inhibitors and transplantation  

PubMed Central

Summary of recent advances Simply detecting the presence or absence of Foxp3, a transcription factor characteristic of naturally occurring CD4+ CD25+ regulatory T cells (Tregs), now appears of minimal value in predicting the outcome of immunologic responses, since dividing human CD4+ effector T cells can induce Foxp3 without attaining repressive functions, and additional molecular interactions, as well epigenetic events, affect Foxp3-dependent Treg functions in humans and mice. Experimentally, in vivo and in vitro studies show histone deacetylase inhibitors (HDACi) can enhance the numbers and suppressive function of regulatory T cells (Tregs), by promoting Foxp3+ cell production, enhancing chromatin remodeling within Tregs, and inducing acetylation of Foxp3 protein itself. Human studies consistent with a role for HDACi in controlling Fox3-dependent Treg functions are also available. We review these molecular interactions and how they may be exploited therapeutically to enhance Treg-dependent functions, including post-transplantation.

Tao, Ran; de Zoeten, Edwin F.; Ozkaynak, Engin; Wang, Liqing; Li, Bin; Greene, Mark I; Wells, Andrew D.; Hancock, Wayne W.

2009-01-01

187

Molecular Modeling Study on Tunnel Behavior in Different Histone Deacetylase Isoforms  

PubMed Central

Histone deacetylases (HDACs) have emerged as effective therapeutic targets in the treatment of various diseases including cancers as these enzymes directly involved in the epigenetic regulation of genes. However the development of isoform-selective HDAC inhibitors has been a challenge till date since all HDAC enzymes possess conserved tunnel-like active site. In this study, using molecular dynamics simulation we have analyzed the behavior of tunnels present in HDAC8, 10, and 11 enzymes of class I, II, and IV, respectively. We have identified the equivalent tunnel forming amino acids in these three isoforms and found that they are very much conserved with subtle differences to be utilized in selective inhibitor development. One amino acid, methionine of HDAC8, among six tunnel forming residues is different in isoforms of other classes (glutamic acid (E) in HDAC10 and leucine (L) in HDAC 11) based on which mutations were introduced in HDAC11, the less studied HDAC isoform, to observe the effects of this change. The HDAC8-like (L268M) mutation in the tunnel forming residues has almost maintained the deep and narrow tunnel as present in HDAC8 whereas HDAC10-like (L268E) mutation has changed the tunnel wider and shallow as observed in HDAC10. These results explained the importance of the single change in the tunnel formation in different isoforms. The observations from this study can be utilized in the development of isoform-selective HDAC inhibitors.

Thangapandian, Sundarapandian; John, Shalini; Lee, Yuno; Arulalapperumal, Venkatesh; Lee, Keun Woo

2012-01-01

188

Dietary Inhibitors of Histone Deacetylases in Intestinal Immunity and Homeostasis  

PubMed Central

Intestinal epithelial cells (IECs) are integral players in homeostasis of immunity and host defense in the gut and are under influence of the intestinal microbiome. Microbial metabolites and dietary components, including short chain fatty acids (acetate, propionate, and butyrate, SCFAs), have an impact on the physiology of IECs at multiple levels, including the inhibition of deacetylases affecting chromatin remodeling and global changes in transcriptional activity. The number and diversity of butyrate-producing bacteria is subject to factors related to age, disease, and to diet. At physiological levels, SCFAs are inhibitors of histone deacetylases (HDACs) which may explain the transcriptional effects of SCFAs on epithelial cells, although many effects of SCFAs on colonic mucosa can be ascribed to mechanisms beyond HDAC inhibition. Interference with this type of post-translational modification has great potential in cancer and different inflammatory diseases, because HDAC inhibition has anti-proliferative and anti-inflammatory effects in vitro, and in in vivo models of intestinal inflammation. Hence, the influence of dietary modulators on HDAC activity in epithelia is likely to be an important determinant of its responses to inflammatory and microbial challenges.

Schilderink, R.; Verseijden, C.; de Jonge, W. J.

2013-01-01

189

Histone Deacetylases 5 and 9 Govern Responsiveness of the Heart to a Subset of Stress Signals and Play Redundant Roles in Heart Development  

Microsoft Academic Search

The adult heart responds to stress signals by hypertrophic growth, which is often accompanied by activation of a fetal cardiac gene program and eventual cardiac demise. We showed previously that histone deacetylase 9 (HDAC9) acts as a suppressor of cardiac hypertrophy and that mice lacking HDAC9 are sensitized to cardiac stress signals. Here we report that mice lacking HDAC5 display

Shurong Chang; Timothy A. McKinsey; Chun Li Zhang; James A. Richardson; Joseph A. Hill; Eric N. Olson

2004-01-01

190

Design and synthesis of CHAP31, trapoxin B and HC-toxin based bicyclic tetrapeptides disulfide as potent histone deacetylase inhibitors.  

PubMed

The naturally occurring cyclic depsipeptide, FK228 inhibits histone deacetylase (HDAC) enzymes after reductive cleavage of intra-molecular disulfide bond. One of the sulfhydryl groups produced in the reduction interacts with zinc atom that involved in the catalytic mechanism of type 1 and 2 HDACs such as HDAC1, HDAC4, and HDAC6. In the present study, we describe the development of CHAP31, trapoxin B and HC-toxin based cyclic tetrapeptides with intra-molecular disulfide bond as HDAC inhibitors. The bicyclic tetrapeptides disulfide showed potent HDAC1 and HDAC4 inhibition and p21 promoting activity. PMID:24997578

Hoque, Md Ashraful; Islam, Md Nurul; Islam, Md Shahidul; Kato, Tamaki; Nishino, Norikazu; Ito, Akihiro; Yoshida, Minoru

2014-08-01

191

Histone acetylases and deacetylases in cell proliferation  

Microsoft Academic Search

There are several enzymes, acetylases and deacetylases, that can regulate transcription by modifying the acetylation state of histones or other promoter-bound transcription factors. Some of these enzymes are present in multisubunit complexes. Recent efforts to understand the biological role of these enzymes reveals their involvement in cell-cycle regulation and differentiation. Furthermore, accumulating evidence suggests that deregulation of acetylase and deacetylase

Tony Kouzarides

1999-01-01

192

Emerin and histone deacetylase 3 (HDAC3) cooperatively regulate expression and nuclear positions of MyoD, Myf5, and Pax7 genes during myogenesis.  

PubMed

The spatial organization of chromatin is critical in establishing cell-type dependent gene expression programs. The inner nuclear membrane protein emerin has been implicated in regulating global chromatin architecture. We show emerin associates with genomic loci of muscle differentiation promoting factors in murine myogenic progenitors, including Myf5 and MyoD. Prior to their transcriptional activation Myf5 and MyoD loci localized to the nuclear lamina in proliferating progenitors and moved to the nucleoplasm upon transcriptional activation during differentiation. The Pax7 locus, which is transcribed in proliferating progenitors, localized to the nucleoplasm and Pax7 moved to the nuclear lamina upon repression during differentiation. Localization of Myf5, MyoD, and Pax7 to the nuclear lamina and proper temporal expression of these genes required emerin and HDAC3. Interestingly, activation of HDAC3 catalytic activity rescued both Myf5 localization to the nuclear lamina and its expression. Collectively, these data support a model whereby emerin facilitates repressive chromatin formation at the nuclear lamina by activating the catalytic activity of HDAC3 to regulate the coordinated spatiotemporal expression of myogenic differentiation genes. PMID:24062260

Demmerle, Justin; Koch, Adam J; Holaska, James M

2013-12-01

193

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.

Marks, Paul A.

2014-01-01

194

Rapid Alteration of MicroRNA Levels by Histone Deacetylase Inhibition  

Microsoft Academic Search

Improved understanding of the molecular mechanisms by which small-molecule inhibitors of histone deacetylases (HDAC) induce programs, such as cellular differentiation and apoptosis, would undoubtedly assist their clinical development as anticancer agents. As modulators of gene transcript levels, HDAC inhibitors (HDACi) typically affect only 5% to 10% of actively transcribed genes with approxi- mately as many mRNA transcripts being up-regulated as

Gary K. Scott; Michael D. Mattie; Crystal E. Berger; Stephen C. Benz; Christopher C. Benz

195

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

Microsoft Academic Search

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

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

2002-01-01

196

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.

Li, Zhiming; Zhu, Wei-Guo

2014-01-01

197

Histone Deacetylase 3 Mediates Allergic Skin Inflammation by Regulating Expression of MCP1 Protein*  

PubMed Central

We have shown the induction of histone deacetylase 3 (HDAC3) in antigen-stimulated rat basophilic leukemia cells via NF-?B. We investigated the role of HDAC3 in allergic skin inflammation. We used a BALB/c mouse model of triphasic cutaneous anaphylaxis (triphasic cutaneous reaction; TpCR) and passive cutaneous anaphylaxis (PCA) to examine the role of HDAC3 in allergic skin inflammation. Triphasic cutaneous reaction involved induction of HDAC3 and was mediated by HDAC3. HDAC3 showed an interaction with Fc?RI?. Trichostatin A (TSA), an inhibitor of HDAC(s), disrupted this interaction. Cytokine array analysis showed that the down-regulation of HDAC3 led to the decreased secretion of monocyte chemoattractant protein 1 (MCP1). Fc?RI was necessary for induction of HDAC3 and MCP1. ChIP assays showed that HDAC3, in association with Sp1 and c-Jun, was responsible for induction of MCP1 expression. TSA exerted a negative effect on induction of MCP1. HDAC3 exerted a negative regulation on expression of HDAC2 via interaction with Rac1. The down-regulation of HDAC3 or inactivation of Rac1 induced binding of HDAC2 to MCP1 promoter sequences. TSA exerted a negative effect on HDAC3-mediated TpCR. The BALB/c mouse model of PCA involved induction of HDAC3 and MCP1. HDAC3 and MCP1 were necessary for PCA that involved ear swelling, enhanced vascular permeability, and angiogenesis. Recombinant MCP1 enhanced ?-hexosaminidase activity and histamine release and also showed angiogenic potential. TSA exerted a negative effect on PCA. Our data show HDAC3 as a valuable target for the development of allergic skin inflammation therapeutics.

Kim, Youngmi; Kim, Kyungjong; Park, Deokbum; Lee, Eunmi; Lee, Hansoo; Lee, Yun-Sil; Choe, Jongseon; Jeoung, Dooil

2012-01-01

198

HDAC6 Is a Bruchpilot Deacetylase that Facilitates Neurotransmitter Release.  

PubMed

Presynaptic densities are specialized structures involved in synaptic vesicle tethering and neurotransmission; however, the mechanisms regulating their function remain understudied. In Drosophila, Bruchpilot is a major constituent of the presynaptic density that tethers vesicles. Here, we show that HDAC6 is necessary and sufficient for deacetylation of Bruchpilot. HDAC6 expression is also controlled by TDP-43, an RNA-binding protein deregulated in amyotrophic lateral sclerosis (ALS). Animals expressing TDP-43 harboring pathogenic mutations show increased HDAC6 expression, decreased Bruchpilot acetylation, larger vesicle-tethering sites, and increased neurotransmission, defects similar to those seen upon expression of HDAC6 and opposite to hdac6 null mutants. Consequently, reduced levels of HDAC6 or increased levels of ELP3, a Bruchpilot acetyltransferase, rescue the presynaptic density defects in TDP-43-expressing flies as well as the decreased adult locomotion. Our work identifies HDAC6 as a Bruchpilot deacetylase and indicates that regulating acetylation of a presynaptic release-site protein is critical for maintaining normal neurotransmission. PMID:24981865

Miskiewicz, Katarzyna; Jose, Liya E; Yeshaw, Wondwossen M; Valadas, Jorge S; Swerts, Jef; Munck, Sebastian; Feiguin, Fabian; Dermaut, Bart; Verstreken, Patrik

2014-07-10

199

Histone Deacetylase Inhibitors and Cognitive Applications.  

National Technical Information Service (NTIS)

The present invention relates to the enhancement of cognition in an individual by delivery of a histone acetylation regulator, such as a histone deacetylase inhibitor. The individual may have normal or poor memory, and the poor memory may be the result of...

J. D. Sweatt J. M. Levenson

2005-01-01

200

Sulforaphane inhibits histone deacetylase in vivo and suppresses tumorigenesis in Apcmin mice  

Microsoft Academic Search

Sulforaphane (SFN) is an isothiocyanate from broccoli that induces phase 2 detoxification enzymes. We recently reported that SFN acts as a histone deacetylase (HDAC) inhibitor in human colon cancer cells in vitro, and the present study sought to extend these findings in vivo. In mice treated with a single oral dose of 10 µmol SFN, there was significant inhibition of

Melinda C. Myzak; W. Mohaiza Dashwood; Gayle A. Orner; Emily Ho; Roderick H. Dashwood

2006-01-01

201

Genomic targets, and histone acetylation and gene expression profiling of neural HDAC inhibition  

PubMed Central

Histone deacetylase inhibitors (HDACis) have been shown to potentiate hippocampal-dependent memory and synaptic plasticity and to ameliorate cognitive deficits and degeneration in animal models for different neuropsychiatric conditions. However, the impact of these drugs on hippocampal histone acetylation and gene expression profiles at the genomic level, and the molecular mechanisms that underlie their specificity and beneficial effects in neural tissue, remains obscure. Here, we mapped four relevant histone marks (H3K4me3, AcH3K9,14, AcH4K12 and pan-AcH2B) in hippocampal chromatin and investigated at the whole-genome level the impact of HDAC inhibition on acetylation profiles and basal and activity-driven gene expression. HDAC inhibition caused a dramatic histone hyperacetylation that was largely restricted to active loci pre-marked with H3K4me3 and AcH3K9,14. In addition, the comparison of Chromatin immunoprecipitation sequencing and gene expression profiles indicated that Trichostatin A-induced histone hyperacetylation, like histone hypoacetylation induced by histone acetyltransferase deficiency, had a modest impact on hippocampal gene expression and did not affect the transient transcriptional response to novelty exposure. However, HDAC inhibition caused the rapid induction of a homeostatic gene program related to chromatin deacetylation. These results illuminate both the relationship between hippocampal gene expression and histone acetylation and the mechanism of action of these important neuropsychiatric drugs.

Lopez-Atalaya, Jose P.; Ito, Satomi; Valor, Luis M.; Benito, Eva; Barco, Angel

2013-01-01

202

Molecular and biologic characterization and drug sensitivity of pan-histone deacetylase inhibitor-resistant acute myeloid leukemia cells  

Microsoft Academic Search

Hydroxamic acid analog pan-histone deacetylase (HDAC) inhibitors (HA-HDIs) have shown preclinical and clinical activ- ity against human acute leukemia. Here we describe HA-HDI-resistant human acute myeloid leukemia (AML) HL-60 (HL- 60\\/LR) cells that are resistant to LAQ824, vorinostat, LBH589, and sodium butyrate. HL-60\\/LR cells show increased expres- sion of HDACs 1, 2, and 4 but lack HDAC6 expression, with concomitant

Warren Fiskus; Rekha Rao; Pravina Fernandez; Bryan Herger; Yonghua Yang; Jianguang Chen; Ravindra Kolhe; Aditya Mandawat; Yongchao Wang; Rajeshree Joshi; Kelly Eaton; Pearl Lee; Peter Atadja; Stephen Peiper; Kapil Bhalla

2008-01-01

203

Histone Deacetylase Inhibitors in Cell Pluripotency, Differentiation, and Reprogramming  

PubMed Central

Histone deacetylase inhibitors (HDACi) are small molecules that have important and pleiotropic effects on cell homeostasis. Under distinct developmental conditions, they can promote either self-renewal or differentiation of embryonic stem cells. In addition, they can promote directed differentiation of embryonic and tissue-specific stem cells along the neuronal, cardiomyocytic, and hepatic lineages. They have been used to facilitate embryo development following somatic cell nuclear transfer and induced pluripotent stem cell derivation by ectopic expression of pluripotency factors. In the latter method, these molecules not only increase effectiveness, but can also render the induction independent of the oncogenes c-Myc and Klf4. Here we review the molecular pathways that are involved in the functions of HDAC inhibitors on stem cell differentiation and reprogramming of somatic cells into pluripotency. Deciphering the mechanisms of HDAC inhibitor actions is very important to enable their exploitation for efficient and simple tissue regeneration therapies.

Kretsovali, Androniki; Hadjimichael, Christiana; Charmpilas, Nikolaos

2012-01-01

204

Histone deacetylase signaling in cardioprotection.  

PubMed

Cardiovascular disease (CVD) represents a major challenge for health care systems, both in terms of the high mortality associated with it and the huge economic burden of its treatment. Although CVD represents a diverse range of disorders, they share common compensatory changes in the heart at the structural, cellular, and molecular level that, in the long term, can become maladaptive and lead to heart failure. Treatment of adverse cardiac remodeling is therefore an important step in preventing this fatal progression. Although previous efforts have been primarily focused on inhibition of deleterious signaling cascades, the stimulation of endogenous cardioprotective mechanisms offers a potent therapeutic tool. In this review, we discuss class I and class II histone deacetylases, a subset of chromatin-modifying enzymes known to have critical roles in the regulation of cardiac remodeling. In particular, we discuss their molecular modes of action and go on to consider how their inhibition or the stimulation of their intrinsic cardioprotective properties may provide a potential therapeutic route for the clinical treatment of CVD. PMID:24310814

Lehmann, Lorenz H; Worst, Barbara C; Stanmore, David A; Backs, Johannes

2014-05-01

205

Downregulation of histone deacetylase 1 by microRNA-520h contributes to the chemotherapeutic effect of doxorubicin.  

PubMed

Doxorubicin induces DNA damage to exert its anti-cancer function. Histone deacetylase 1 (HDAC1) can protect the genome from DNA damage. We found that doxorubicin specifically downregulates HDAC1 protein expression and identified HDAC1 as a target of miR-520h, which was upregulated by doxorubicin. Doxorubicin-induced cell death was impaired by exogenous HDAC1 or by miR-520h inhibitor. Moreover, HDAC1 reduced the level of ?H2AX by preventing the interaction of doxorubicin with DNA. In summary, doxorubicin downregulates HDAC1 protein expression, by inducing the expression of HDAC1-targeting miR-520h, to exacerbate DNA-doxorubicin interaction. The upregulation of HDAC1 protein may contribute to drug resistance of human cancer cells and targeting HDAC1 is a promising strategy to increase the clinical efficacy of DNA damage-inducing chemotherapeutic drugs. PMID:24316511

Shen, Qi; Yao, Qinghua; Sun, Jie; Feng, Lifeng; Lu, Haiqi; Ma, Yanning; Liu, Leiming; Wang, Faliang; Li, Jiaqiu; Yue, Yongfang; Jin, Hongchuan; Wang, Xian

2014-01-01

206

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

207

Class II Human Histone Deacetylases, and Uses Related Thereto.  

National Technical Information Service (NTIS)

The invention provides histone deacetylase class II nucleic acids and polypeptides, methods and reagents for their use, and related compounds including small molecule libraries containing class II histone deacetylase inhibitors.

C. A. Hassig C. M. Grozinger S. L. Schreiber

2004-01-01

208

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

PubMed Central

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

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

2013-01-01

209

14-3-3 regulates the nuclear import of class IIa histone deacetylases  

SciTech Connect

Class IIa histone deacetylases (HDACs) form complexes with a class of transcriptional repressors in the nucleus. While screening for compounds that could block the association of HDAC4 with the BTB domain-containing transcriptional repressor Bach2, we discovered that phorbol 12-myristate 13-acetate (PMA) induced the cytoplasmic retention of HDAC4 mutants lacking a nuclear export signal (NES). Although PMA treatment and PKD overexpression has been proposed to facilitate the nuclear export of class IIa HDACs by creating 14-3-3 binding sites containing phosphoserines, our experiments using HDAC mutants demonstrated that PMA greatly reduces nuclear import. PMA treatment repressed the NLS activity in a manner dependent on 14-3-3 binding. These results suggest that nuclear HDAC4 is not tethered in the nucleus, but instead shuttles between the nucleus and the cytoplasm. Phosphorylation-induced 14-3-3 binding biases the balance of nucleo-cytoplasmic shuttling toward the cytoplasm by inhibiting nuclear import.

Nishino, Tomonori G. [Chemical Genetics Laboratory/Chemical Genomics Research Group, RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198 (Japan); Department of Biotechnology, University of Tokyo, Bunkyo-ku, Tokyo 113-8657 (Japan); Miyazaki, Masaya [Department of Biotechnology, University of Tokyo, Bunkyo-ku, Tokyo 113-8657 (Japan); Hoshino, Hideto [Department of Biotechnology, University of Tokyo, Bunkyo-ku, Tokyo 113-8657 (Japan); Japan Science and Technology Corporation (JST), CREST Research Project, 5-sanbancho, Chiyodaku, Tokyo 102-0075 (Japan); Miwa, Yoshihiro [Department of Molecular Pharmacology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, 305-8575 (Japan); JST, PRESTO Research Project, Kawaguchi, Saitama 332-0012 (Japan); Horinouchi, Sueharu [Department of Biotechnology, University of Tokyo, Bunkyo-ku, Tokyo 113-8657 (Japan); Yoshida, Minoru [Chemical Genetics Laboratory/Chemical Genomics Research Group, RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198 (Japan); Department of Biotechnology, University of Tokyo, Bunkyo-ku, Tokyo 113-8657 (Japan); Japan Science and Technology Corporation (JST), CREST Research Project, 5-sanbancho, Chiyodaku, Tokyo 102-0075 (Japan)], E-mail: yoshidam@riken.jp

2008-12-19

210

Boric acid inhibits embryonic histone deacetylases: A suggested mechanism to explain boric acid-related teratogenicity  

SciTech Connect

Histone deacetylases (HDAC) control gene expression by changing histonic as well as non histonic protein conformation. HDAC inhibitors (HDACi) are considered to be among the most promising drugs for epigenetic treatment for cancer. Recently a strict relationship between histone hyperacetylation in specific tissues of mouse embryos exposed to two HDACi (valproic acid and trichostatin A) and specific axial skeleton malformations has been demonstrated. The aim of this study is to verify if boric acid (BA), that induces in rodents malformations similar to those valproic acid and trichostatin A-related, acts through similar mechanisms: HDAC inhibition and histone hyperacetylation. Pregnant mice were treated intraperitoneally with a teratogenic dose of BA (1000 mg/kg, day 8 of gestation). Western blot analysis and immunostaining were performed with anti hyperacetylated histone 4 (H4) antibody on embryos explanted 1, 3 or 4 h after treatment and revealed H4 hyperacetylation at the level of somites. HDAC enzyme assay was performed on embryonic nuclear extracts. A significant HDAC inhibition activity (compatible with a mixed type partial inhibition mechanism) was evident with BA. Kinetic analyses indicate that BA modifies substrate affinity by a factor {alpha} = 0.51 and maximum velocity by a factor {beta} = 0.70. This work provides the first evidence for HDAC inhibition by BA and suggests such a molecular mechanism for the induction of BA-related malformations.

Di Renzo, Francesca [Department of Biology, University of Milan, Via Celoria, 26. 20133 Milan (Italy); Cappelletti, Graziella [Department of Biology, University of Milan, Via Celoria, 26. 20133 Milan (Italy); Broccia, Maria L. [Department of Biology, University of Milan, Via Celoria, 26. 20133 Milan (Italy); Giavini, Erminio [Department of Biology, University of Milan, Via Celoria, 26. 20133 Milan (Italy); Menegola, Elena [Department of Biology, University of Milan, Via Celoria, 26. 20133 Milan (Italy)]. E-mail: elena.menegola@unimi.it

2007-04-15

211

BRCA1 interacts with components of the histone deacetylase complex.  

PubMed

Germ-line mutations in the BRCA1 tumor-suppressor gene are associated with an increased susceptibility to breast and ovarian cancer. BRCA1 contains a carboxyl-terminal domain (BRCT) that is shared with several other proteins involved in maintaining genome integrity. In an effort to understand the function of BRCA1, we sought to isolate proteins that interact with the BRCT domain. Purified BRCT polypeptide was used as a probe to screen a human placenta cDNA expression library by Far Western analysis. Here we report that BRCA1 interacts in vivo and in vitro with the Rb-binding proteins, RbAp46 and RbAp48, as well as with Rb. Moreover, the BRCT domain associates with the histone deacetylases HDAC1 and HDAC2. These results demonstrate that BRCA1 interacts with components of the histone deacetylase complex, and therefore may explain the involvement of BRCA1 in multiple processes such as transcription, DNA repair, and recombination. PMID:10220405

Yarden, R I; Brody, L C

1999-04-27

212

Histone deacetylases in herpesvirus replication and virus-stimulated host defense.  

PubMed

Emerging evidence highlights a critical role for protein acetylation during herpesvirus infection. As prominent modulators of protein acetylation, histone deacetylases (HDACs) are essential transcriptional and epigenetic regulators. Not surprisingly, viruses have evolved a wide array of mechanisms to subvert HDAC functions. Here, we review the mechanisms underlying HDAC regulation during herpesvirus infection. We next discuss the roles of acetylation in host defense against herpesvirus infection. Finally, we provide a perspective on the contribution of current mass spectrometry-based "omic" technologies to infectious disease research, offering a systems biology view of infection. PMID:23807710

Guise, Amanda J; Budayeva, Hanna G; Diner, Benjamin A; Cristea, Ileana M

2013-07-01

213

The clinical development of histone deacetylase inhibitors as targeted anticancer drugs  

PubMed Central

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

Marks, Paul A

2014-01-01

214

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

Microsoft Academic Search

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

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

2007-01-01

215

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

216

A Novel Histone Deacetylase Inhibitor Exhibits Antitumor Activity via Apoptosis Induction, F-Actin Disruption and Gene Acetylation in Lung Cancer  

Microsoft Academic Search

BackgroundLung cancer is the leading cause of cancer mortality worldwide, yet the therapeutic strategy for advanced non-small cell lung cancer (NSCLC) is limitedly effective. In addition, validated histone deacetylase (HDAC) inhibitors for the treatment of solid tumors remain to be developed. Here, we propose a novel HDAC inhibitor, OSU-HDAC-44, as a chemotherapeutic drug for NSCLC.Methodology\\/Principal FindingsThe cytotoxicity effect of OSU-HDAC-44

Yen-An Tang; Wei-Ling Wen; Jer-Wei Chang; Tzi-Tang Wei; Yi-Hung Carol Tan; Santosh Salunke; Chien-Tien Chen; Ching-Shih Chen; Yi-Ching Wang; Chun-Ming Wong

2010-01-01

217

Synthesis and modeling of new benzofuranone histone deacetylase inhibitors that stimulate tumor suppressor gene expression.  

PubMed

New benzofuranones were synthesized and evaluated toward NCI-H661 non-small cell lung cancer cells. Benzamide derivatives possessed micromolar antiproliferative and histone deacetylase inhibitory activities and modulate histone H4 acetylation. Hydroxamic acids were found to be potent nanomolar antiproliferative agents and HDAC inhibitors. Computational analysis presented a rationale for the activities of the hydroxamate derivatives. Impact of the HDAC inhibition on the expression of E-cadherin and the SEMA3F tumor suppressor genes revealed new promising compounds for lung cancer treatments. PMID:19385600

Charrier, Cédric; Clarhaut, Jonathan; Gesson, Jean-Pierre; Estiu, Guillermina; Wiest, Olaf; Roche, Joëlle; Bertrand, Philippe

2009-05-14

218

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

PubMed Central

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

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

2011-01-01

219

Microtubule-associated deacetylase HDAC6 promotes angiogenesis by regulating cell migration in an EB1-dependent manner  

Microsoft Academic Search

Angiogenesis, a process by which the preexisting blood vasculature gives rise to new capillary vessels, is associated with\\u000a a variety of physiologic and pathologic conditions. However, the molecular mechanism underlying this important process remains\\u000a poorly understood. Here we show that histone deacetylase 6 (HDAC6), a microtubule-associated enzyme critical for cell motility,\\u000a contributes to angiogenesis by regulating the polarization and migration

Dengwen Li; Songbo Xie; Yuan Ren; Lihong Huo; Jinmin Gao; Dandan Cui; Min Liu; Jun Zhou

2011-01-01

220

Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation.  

PubMed

ATP-dependent nucleosome remodeling and core histone acetylation and deacetylation represent mechanisms to alter nucleosome structure. NuRD is a multisubunit complex containing nucleosome remodeling and histone deacetylase activities. The histone deacetylases HDAC1 and HDAC2 and the histone binding proteins RbAp48 and RbAp46 form a core complex shared between NuRD and Sin3-histone deacetylase complexes. The histone deacetylase activity of the core complex is severely compromised. A novel polypeptide highly related to the metastasis-associated protein 1, MTA2, and the methyl-CpG-binding domain-containing protein, MBD3, were found to be subunits of the NuRD complex. MTA2 modulates the enzymatic activity of the histone deacetylase core complex. MBD3 mediates the association of MTA2 with the core histone deacetylase complex. MBD3 does not directly bind methylated DNA but is highly related to MBD2, a polypeptide that binds to methylated DNA and has been reported to possess demethylase activity. MBD2 interacts with the NuRD complex and directs the complex to methylated DNA. NuRD may provide a means of gene silencing by DNA methylation. PMID:10444591

Zhang, Y; Ng, H H; Erdjument-Bromage, H; Tempst, P; Bird, A; Reinberg, D

1999-08-01

221

Toward isozyme-selective inhibitors of histone deacetylase as therapeutic agents for the treatment of cancer  

PubMed Central

Since post-translational modifications of proteins are key mechanisms for controlling cellular function, targeting the machinery involved in these modifications offers new opportunities for the development of therapeutic agents. The histone deacetylases (HDACs) represent an important family of enzymes that are involved in controlling the acetylation state of key lysine residues in histones and other proteins. The development of HDAC inhibitors for the treatment of several diseases, most notably cancer, has proceeded rapidly. Recent attention has turned towards the development of isozyme-specific inhibitors that will provide selective targeting. It is believed that the ability to target-specific HDACs rather than all family members will lead to superior therapeutics with better efficacy and lower toxicity. A review of recent patents shows that researchers are targeting a wide range of isozymes and that key advances in the structural biology of HDACs are providing important design information.

Ononye, Sophia N; van Heyst, Michael; Falcone, Eric M; Anderson, Amy C; Wright, Dennis L

2013-01-01

222

4-Phenylbutyric acid protects against neuronal cell death by primarily acting as a chemical chaperone rather than histone deacetylase inhibitor.  

PubMed

This letter describes the mechanism behind the protective effect of 4-phenylbutyric acid (4-PBA) against endoplasmic reticulum (ER) stress-induced neuronal cell death using three simple 4-(p-substituted phenyl) butyric acids (4-PBA derivatives). Their relative human histone deacetylase (HDAC) inhibitory activities were consistent with a structural model of their binding to HDAC7, and their ability to suppress neuronal cell death and activity of chemical chaperone in vitro. These data suggest that 4-PBA protects against neuronal cell death mediated by the chemical chaperone activity rather than by inhibition of histone deacetylase. PMID:24044874

Mimori, Seisuke; Ohtaka, Hiroyasu; Koshikawa, Yukari; Kawada, Koichi; Kaneko, Masayuki; Okuma, Yasunobu; Nomura, Yasuyuki; Murakami, Yasuoki; Hamana, Hiroshi

2013-11-01

223

?-Keto amides as inhibitors of histone deacetylase  

Microsoft Academic Search

?-Keto ester and amides were found to be potent inhibitors of histone deacetylase. Nanomolar inhibitors against the isolated enzyme and sub-micromolar inhibitors of cellular proliferation were obtained. The alpha-keto amide 30 also exhibited significant anti-tumor effects in an in vivo tumor model.

Carol K. Wada; Robin R. Frey; Zhiqin Ji; Michael L. Curtin; Robert B. Garland; James H. Holms; Junling Li; Lori J. Pease; Jun Guo; Keith B. Glaser; Patrick A. Marcotte; Paul L. Richardson; Shannon S. Murphy; Jennifer J. Bouska; Paul Tapang; Terrance J. Magoc; Daniel H. Albert; Steven K. Davidsen; Michael R. Michaelides

2003-01-01

224

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

PubMed Central

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

Kim, Hyun-Jung; Bae, Suk-Chul

2011-01-01

225

Development of N-Hydroxycinnamamide-Based Histone Deacetylase Inhibitors with Indole-Containing Cap Group  

PubMed Central

A novel series of histone deacetylase inhibitors combining N-hydroxycinnamamide bioactive fragment and indole bioactive fragment was designed and synthesized. Several compounds (17c, 17g, 17h, 17j and 17k) exhibited comparable even superior total HDACs inhibitory activity and in vitro antiproliferative activities relative to the approved drug SAHA. A representative compound 17a with moderate HDACs inhibition was progressed to isoform selectivity profile, western blot analysis and in vivo antitumor assay. Although HDACs isoform selectivity of 17a was similar to that of SAHA, our western blot results indicated that intracellular effects of 17a at 1 ?M were class I selective. It was noteworthy that the effect on histone H4 acetylation of SAHA decreased with time while the effect on histone H4 acetylation of 17a maintained even increased. Most importantly, compound 17a exhibited promising in vivo antitumor activity in a U937 xenograft model.

Zhang, Yingjie; Yang, Penghui; Chou, C. James; Liu, Chunxi; Wang, Xuejian; Xu, Wenfang

2013-01-01

226

Histone deacetylase 1 is required for exocrine pancreatic epithelial proliferation in development and cancer  

PubMed Central

Histone deacetylases (HDACs) play important roles in the epigenetic control of development and aberrant expression of HDACs has been implicated in human diseases including cancer. Among the mammalian HDACs, HDAC1 has been extensively studied, but its role in exocrine pancreatic morphogenesis and cancer is still poorly understood. The goal of this study is to determine the functional role of HDAC1 in normal development of exocrine pancreas using zebrafish as the model organism as well as in human pancreatic adenocarcinoma. The zebrafish germline loss-of-function mutation hdac1hi1618 caused impaired cell cycle progression in pancreatic epithelia, resulting in growth arrest and dysmorphogenesis of exocrine pancreas. In human pancreatic adenocarcinoma tissues and cell lines, HDAC1 was expressed at variably elevated levels. RNA interference-induced silencing of HDAC1 diminished proliferation of the cancer cells and cell cycle progression. The proliferative arrest in the developing exocrine pancreas and pancreatic cancer cells was associated with upregulated expression of the cyclin-dependent kinase inhibitors and the sonic hedgehog signaling components. This study indicates that HDAC1 is required for pancreatic epithelial proliferation in development and cancer. We hypothesize that aberrant expression of HDAC1 modulates the developmental and signaling pathways in exocrine pancreatic epithelia and consequently the genes required for cellular proliferation during development and progression of pancreatic neoplasia.

2011-01-01

227

Histone Deacetylase 8 Is Required for Centrosome Cohesion and Influenza A Virus Entry  

PubMed Central

Influenza A virus (IAV) enters host cells by endocytosis followed by acid-activated penetration from late endosomes (LEs). Using siRNA silencing, we found that histone deacetylase 8 (HDAC8), a cytoplasmic enzyme, efficiently promoted productive entry of IAV into tissue culture cells, whereas HDAC1 suppressed it. HDAC8 enhanced endocytosis, acidification, and penetration of the incoming virus. In contrast, HDAC1 inhibited acidification and penetration. The effects were connected with dramatic alterations in the organization of the microtubule system, and, as a consequence, a change in the behavior of LEs and lysosomes (LYs). Depletion of HDAC8 caused loss of centrosome-associated microtubules and loss of directed centripetal movement of LEs, dispersing LE/LYs to the cell periphery. For HDAC1, the picture was the opposite. To explain these changes, centrosome cohesion emerged as the critical factor. Depletion of HDAC8 caused centrosome splitting, which could also be induced by depleting a centriole-linker protein, rootletin. In both cases, IAV infection was inhibited. HDAC1 depletion reduced the splitting of centrosomes, and enhanced infection. The longer the distance between centrosomes, the lower the level of infection. HDAC8 depletion was also found to inhibit infection of Uukuniemi virus (a bunyavirus) suggesting common requirements among late penetrating enveloped viruses. The results established class I HDACs as powerful regulators of microtubule organization, centrosome function, endosome maturation, and infection by IAV and other late penetrating viruses.

Yamauchi, Yohei; Boukari, Heithem; Banerjee, Indranil; Sbalzarini, Ivo F.; Horvath, Peter; Helenius, Ari

2011-01-01

228

Synthesis of N-hydroxycinnamides capped with a naturally occurring moiety as inhibitors of histone deacetylase.  

PubMed

Histone deacetylase (HDAC) inhibitors are regarded as promising therapeutics for the treatment of cancer. All reported HDAC inhibitors contain three pharmacophoric features: a zinc-chelating group, a hydrophobic linker, and a hydrophobic cap for surface recognition. In this study we investigated the effectiveness of osthole, a hydrophobic Chinese herbal compound, as the surface recognition cap in hydroxamate-based compounds as inhibitors of HDAC. Nine novel osthole-based N-hydroxycinnamides were synthesized and screened for enzyme inhibition activity. Compounds 9 d, 9 e, 9 g exhibited inhibitory activities (IC(50)=24.5, 20.0, 19.6 nM) against nuclear HDACs in HeLa cells comparable to that of suberoylanilide hydroxamic acid (SAHA; IC(50)=24.5 nM), a potent inhibitor clinically used for the treatment of cutaneous T-cell lymphoma (CTCL). While compounds 9 d and 9 e showed SAHA-like activity towards HDAC1 and HDAC6, compound 9 g was more selective for HDAC1. Compound 9 d exhibited the best cellular effect, which was comparable to that of SAHA, of enhancing acetylation of either alpha-tubulin or histone H3. Molecular docking analysis showed that the osthole moiety of compound 9 d may interact with the same hydrophobic surface pocket exploited by SAHA and it may be modified to provide class-specific selectivity. These results suggest that osthole is an effective hydrophobic cap when incorporated into N-hydroxycinnamide-derived HDAC inhibitors. PMID:20209563

Huang, Wei-Jan; Chen, Ching-Chow; Chao, Shi-Wei; Lee, Shoei-Sheng; Hsu, Fen-Lin; Lu, Yeh-Lin; Hung, Ming-Fang; Chang, Chung-I

2010-04-01

229

Depudecin induces morphological reversion of transformed fibroblasts via the inhibition of histone deacetylase  

PubMed Central

Depudecin is a fungal metabolite that reverts the rounded phenotype of NIH 3T3 fibroblasts transformed with v-ras and v-src oncogenes to the flattened phenotype of the nontransformed parental cells. The mechanism of detransformation induced by this agent had not been determined. Here, we demonstrate that depudecin inhibits histone deacetylase (HDAC) activity effectively both in vivo and in vitro. Depudecin induces similar morphological reversion in v-ras transformed NIH 3T3 cells as do other naturally occurring HDAC inhibitors such as trichostatin A or trapoxin. It competitively inhibits the binding of [3H]trapoxin in vitro and the nuclear binding of a trapoxin–coumarin fluorophore in vivo, suggesting that depudecin shares a nuclear binding protein and site on that protein with trapoxin. Furthermore, depudecin induces hyperacetylation of histones in a dose-dependent manner and at concentrations comparable with that required for detransformation. An in vitro histone deacetylase assay, using purified recombinant HDAC1, reveals that depudecin inhibits 50% of the enzyme activity at a concentration of 4.7 ?M. These results demonstrate that depudecin is a novel HDAC inhibitor and suggest that its ability to induce morphological reversion of transformed cells is the result of its HDAC inhibitory activity.

Kwon, Ho Jeong; Owa, Takashi; Hassig, Christian A.; Shimada, Junichi; Schreiber, Stuart L.

1998-01-01

230

Structural origin of selectivity in class II-selective histone deacetylase inhibitors.  

PubMed

The development of class- and isoform-selective histone deacetylase (HDAC) inhibitors is highly desirable for the study of the complex interactions of these proteins central to transcription regulation as well as for the development of selective HDAC inhibitors as drugs in epigenetics. To provide a structural basis for the rational design of such inhibitors, a combined computational and experimental study of inhibition of three different histone deacetylase isoforms, HDAC1, -6, and -8, with three different hydroxamate inhibitors is reported. While SAHA was found to be unselective for the inhibition of class I and class II HDACs, the other inhibitors were found to be selective toward class II HDACs. Molecular dynamics simulations indicate that this selectivity is caused by both the overall shape of the protein surface leading to the active site and specific interactions of an aspartate residue in a polar loop and two phenylalanines and a methionine in a nonpolar loop. Monitoring the specific interactions as a function of the simulation time identifies a key sulfur-pi interaction. The implications of the structural motifs for the design of class II-selective HDAC inhibitors are discussed. PMID:18412327

Estiu, Guillermina; Greenberg, Edward; Harrison, Christopher B; Kwiatkowski, Nicholas P; Mazitschek, Ralph; Bradner, James E; Wiest, Olaf

2008-05-22

231

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

232

The Biology of HDAC3  

Microsoft Academic Search

Histone deacetylase 3 (HDAC3) is one of four members of the human class I histone deacetylases that repress transcription\\u000a by deacetylation of histones. This review describes our current knowledge regarding its structure, function, mechanisms of\\u000a action, and regulation.

Edward Seto

233

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

234

The epigenetic regulator Histone Deacetylase 1 promotes transcription of a core neurogenic programme in zebrafish embryos  

PubMed Central

Background The epigenetic regulator Histone Deacetylase 1 (Hdac1) is required for specification and patterning of neurones and myelinating glia during development of the vertebrate central nervous system (CNS). This co-ordinating function for Hdac1 is evolutionarily conserved in zebrafish and mouse, but the mechanism of action of Hdac1 in the developing CNS is not well-understood. Results A genome-wide comparative analysis of the transcriptomes of Hdac1-deficient and wild-type zebrafish embryos was performed, which identified an extensive programme of gene expression that is regulated by Hdac1 in the developing embryo. Using time-resolved expression profiling of embryos, we then identified a small subset of 54 genes within the Hdac1-regulated transcriptome that specifically exhibit robust and sustained Hdac1-dependent expression from early neurogenesis onwards. 18 of these 54 stringently Hdac1-regulated genes encode DNA-binding transcription factors that are implicated in promoting neuronal specification and CNS patterning, including the proneural bHLH proteins Ascl1a and Ascl1b, as well as Neurod4 and Neurod. Relatively few genes are strongly repressed by Hdac1 but expression of the Notch target gene her6 is attenuated by Hdac1 in specific sub-regions of the developing CNS, from early stages of neurogenesis onwards. Selected members of the stringently Hdac1-regulated group of genes were tested for Hdac1 binding to their promoter-proximal cis-regulatory elements. Surprisingly, we found that Hdac1 is specifically and stably associated with DNA sequences within the promoter region of ascl1b during neurogenesis, and that this Hdac1-ascl1b interaction is abolished in hdac1 mutant embryos. Conclusions We conclude that Hdac1 regulates histone acetylation and methylation in the developing zebrafish embryo and promotes the sustained, co-ordinate transcription of a small set of transcription factor genes that control expansion and diversification of cell fates within the developing CNS. Our in vivo chromatin immunoprecipitation results also suggest a specific function for Hdac1 in directly regulating transcription of a key member of this group of genes, ascl1b, from the beginning of neurogenesis onwards. Taken together, our observations indicate a novel role for Hdac1 as a positive regulator of gene transcription during development of the vertebrate CNS, in addition to its more well-established function in transcriptional repression.

2011-01-01

235

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.

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

2013-01-01

236

Histone deacetylase 5 blocks neuroblastoma cell differentiation by interacting with N-Myc.  

PubMed

The N-Myc oncoprotein induces neuroblastoma, which arises from undifferentiated neuroblasts in the sympathetic nervous system, by modulating gene and protein expression and consequently causing cell differentiation block and cell proliferation. The class IIa histone deacetylase 5 (HDAC5) represses gene transcription, and blocks myoblast, osteoblast and leukemia cell differentiation. Here we showed that N-Myc upregulated HDAC5 expression in neuroblastoma cells. Conversely, HDAC5 repressed the ubiquitin-protein ligase NEDD4 gene expression, increased Aurora A gene expression and consequently upregulated N-Myc protein expression. Genome-wide gene expression analysis and protein co-immunoprecipitation assays revealed that HDAC5 and N-Myc repressed the expression of a common subset of genes by forming a protein complex, whereas HDAC5 and the class III HDAC SIRT2 independently repressed the expression of another common subset of genes without forming a protein complex. Moreover, HDAC5 blocked differentiation and induced proliferation in neuroblastoma cells. Taken together, our data identify HDAC5 as a novel co-factor in N-Myc oncogenesis, and provide the evidence for the potential application of HDAC5 inhibitors in the therapy of N-Myc-induced neuroblastoma and potentially other c-Myc-induced malignancies. PMID:23812427

Sun, Y; Liu, P Y; Scarlett, C J; Malyukova, A; Liu, B; Marshall, G M; MacKenzie, K L; Biankin, A V; Liu, T

2014-06-01

237

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

PubMed

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

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

2011-01-01

238

Regulation of Skeletal Myogenesis by Association of the MEF2 Transcription Factor with Class II Histone Deacetylases  

Microsoft Academic Search

Skeletal muscle differentiation is controlled by associations between myogenic basic-helix-loop-helix and MEF2 transcription factors. We show that chromatin associated with muscle genes regulated by these transcription factors becomes acetylated during myogenesis and that class II histone deacetylases (HDACs), which interact with MEF2, specifically suppress myoblast differentiation. These HDACs do not interact directly with MyoD, yet they suppress its myogenic activity

Jianrong Lu; Timothy A. McKinsey; Chun-Li Zhang; Eric N. Olson

2000-01-01

239

Inhibitors of Histone Deacetylase Relieve ETO-mediated Repression and Induce Differentiation of AML1ETO Leukemia Cells  

Microsoft Academic Search

The (8;21) translocation, found in 12% of acute myeloid leukemia (AML), creates the chimeric fusion product, AML1-ETO. Previously, we demonstrated that the ETO moiety recruits a transcription repression complex that includes the histone deacetylase (HDAC1) enzyme. Here, we used inhibitors of HDAC1 to study the pathophysiology of AML1-ETO. Both the potent inhibitor, trichostatin (TSA), and the well-known but less specific

Jianxiang Wang; Yogen Saunthararajah; Robert L. Redner; Johnson M. Liu

1999-01-01

240

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

PubMed Central

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

2012-01-01

241

Neuronal apoptosis induced by histone deacetylase inhibitors.  

PubMed

Histone acetylation has a key role in transcriptional activation, whereas deacetylation of histones correlates with the transcriptional repression and silencing of genes. Genetic repression may have an important role in neuronal aging, atrophy and degenerative diseases. Our aim was to study how histone deacetylase inhibitors, trichostatin A (TSA) and sodium butyrate, affect the metabolism of cultured rat cerebellar granule neurons and mouse Neuro-2a neuroblastoma cells. Cultured cells were exposed to 1-3 microM TSA and 1-10 mM butyrate for 1-2 days. Both of these inhibitors induced a prominent neuronal apoptosis characterized by morphological changes as well as by the activation of caspase-3 protease and subsequent cleavage of poly(ADP-ribose) polymerase, one of the caspase-3 targets. Caspase-3 activities reached the highest level on the second day after treatment, higher in the proliferating neuroblastoma cells than in the cerebellar granule neurons. Caspase-3 activation and morphological changes were prevented by cycloheximide treatment. Histone deacetylase inhibitors increased the DNA-binding activities of AP1, CREB and NF-kappaB transcription factors. These observations show that an excessive level of histone acetylation induces a stress response and an apoptotic cell death in neuronal cells. PMID:9795219

Salminen, A; Tapiola, T; Korhonen, P; Suuronen, T

1998-10-30

242

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.

2012-01-01

243

Histone deacetylase complex1 expression level titrates plant growth and abscisic acid sensitivity in Arabidopsis.  

PubMed

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

2013-09-01

244

Suppression of Class I and II Histone Deacetylases Blunts Pressure-Overload Cardiac Hypertrophy  

PubMed Central

Background Recent work has demonstrated the importance of chromatin remodeling, especially histone acetylation, in the control of gene expression in the heart. In cell culture models of cardiac hypertrophy, pharmacological suppression of histone deacetylases (HDACs) can either blunt or amplify cell growth. Thus, HDAC inhibitors hold promise as potential therapeutic agents in hypertrophic heart disease. Methods and Results In the present investigation, we studied 2 broad-spectrum HDAC inhibitors in a physiologically relevant banding model of hypertrophy, observing dose-responsive suppression of ventricular growth that was well tolerated in terms of both clinical outcome and cardiac performance measures. In both short-term (3-week) and long-term (9-week) trials, cardiomyocyte growth was blocked by HDAC inhibition, with no evidence of cell death or apoptosis. Fibrotic change was diminished in hearts treated with HDAC inhibitors, and collagen synthesis in isolated cardiac fibroblasts was blocked. Preservation of systolic function in the setting of blunted hypertrophic growth was documented by echocardiography and by invasive pressure measurements. The hypertrophy-associated switch of adult and fetal isoforms of myosin heavy chain expression was attenuated, which likely contributed to the observed preservation of systolic function in HDAC inhibitor–treated hearts. Conclusions Together, these data suggest that HDAC inhibition is a viable therapeutic strategy that holds promise in the treatment of load-induced heart disease.

Kong, Yongli; Tannous, Paul; Lu, Guangrong; Berenji, Kambeez; Rothermel, Beverly A.; Olson, Eric N.; Hill, Joseph A.

2014-01-01

245

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

246

Immune regulation by histone deacetylases: a focus on the alteration of FOXP3 activity  

Microsoft Academic Search

Several histone deacetylases (HDACs) are involved in the regulation of forkhead box protein P3 (FOXP3) expression and function by affecting features of FOXP3 protein stability. FOXP3, a forkhead family transcription factor specially expressed in regulatory T (Treg) cells, controls the expression of many key immune-regulatory genes. Treg cells are a population of T lymphocytes that have critical roles in the

Hongtao Zhang; Yan Xiao; Zhiqiang Zhu; Bin Li; Mark I Greene

2012-01-01

247

Design and campaign synthesis of piperidine- and thiazole-based histone deacetylase inhibitors.  

PubMed

A lead benzamide, 3, was identified as a potent and low molecular weight histone deacetylase (HDAC) inhibitor. Optimization led to 16d, demonstrating an excellent balance of efficacy and non-efficacy properties, along with very desirable in vivo DMPK. The final compounds presented are >1000-fold more potent than the initial screen hit, an improvement in potency which was achieved with a concomitant significant improvement in all the main non-efficacy properties. PMID:18378449

Andrews, David M; Stokes, Elaine S E; Carr, Greg R; Matusiak, Zbigniew S; Roberts, Craig A; Waring, Michael J; Brady, Madeleine C; Chresta, Christine M; East, Simon J

2008-04-15

248

SLC5A8 Triggers Tumor Cell Apoptosis through Pyruvate-Dependent Inhibition of Histone Deacetylases  

Microsoft Academic Search

Tumor cells up-regulate glycolysis but convert pyruvate into lactate instead of oxidizing it. Here, we show that pyruvate, but not lactate, is an inhibitor of histone deacetylases (HDAC) and an inducer of apoptosis in tumor cells and that SLC5A8, aN a +\\/monocarboxylate cotransporter, is obligatory for this process. We found that SLC5A8 is expressed in nontrans- formed breast epithelial cell

Muthusamy Thangaraju; Elangovan Gopal; Pamela M. Martin; Sudha Ananth; Sylvia B. Smith; Puttur D. Prasad; Esta Sterneck; Vadivel Ganapathy

249

Transcriptional therapy with the histone deacetylase inhibitor trichostatin A ameliorates experimental autoimmune encephalomyelitis  

Microsoft Academic Search

We demonstrate that the histone deacetylase (HDAC) inhibitor drug trichostatin A (TSA) reduces spinal cord inflammation, demyelination, neuronal and axonal loss and ameliorates disability in the relapsing phase of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). TSA up-regulates antioxidant, anti-excitotoxicity and pro-neuronal growth and differentiation mRNAs. TSA also inhibits caspase activation and down-regulates gene targets of the

Sandra Camelo; Antonio H. Iglesias; Daehee Hwang; Brice Due; Hoon Ryu; Karen Smith; Steven G. Gray; Jaime Imitola; German Duran; Basel Assaf; Brett Langley; Samia J. Khoury; George Stephanopoulos; Umberto De Girolami; Rajiv R. Ratan; Robert J. Ferrante; Fernando Dangond

2005-01-01

250

Signal-dependent activation of the MEF2 transcription factor by dissociation from histone deacetylases  

Microsoft Academic Search

Myocyte enhancer factor-2 (MEF2) transcription factors control muscle-specific and growth factor-inducible genes. We show that hypertrophic growth of cardiomyocytes in response to phenylephrine and serum is accompanied by activation of MEF2 through a posttranslational mechanism mediated by calcium, calmodulin-dependent protein kinase (CaMK), and mitogen-activated protein kinase (MAPK) signaling. CaMK stimulates MEF2 activity by dissociating class II histone deacetylases (HDACs) from

Jianrong Lu; Timothy A. McKinsey; Rebekka L. Nicol; Eric N. Olson

2000-01-01

251

Silencing of transcription of the human luteinizing hormone receptor gene by histone deacetylase-mSin3A complex.  

PubMed

Modification of chromatin structure by histone acetylases and deacetylases is an important mechanism in modulation of eukaryotic gene transcription. The present study investigated regulation of the human luteinizing hormone receptor (hLHR) gene by histone deacetylases. Inhibition of histone deacetylases (HDACs) by trichostatin A (TSA) increased hLHR promoter activity by 40-fold in JAR cells and markedly elevated endogenous hLHR mRNA levels. Acetylated histones H3 and H4 accumulated in TSA-treated cells and associated predominantly with the hLHR promoter. Furthermore, TSA significantly enhanced the recruitment of RNA polymerase II to the promoter. One of the two Sp1 sites essential for basal promoter activity was identified as critical for the TSA effect, but the binding of Sp1/Sp3 to this site remained unchanged in the absence or presence of TSA. A multiprotein complex was recruited to the hLHR promoter via interaction with Sp1 and Sp3, in which HDAC1 and HDAC2 were docked directly to Sp1-bound DNA and indirectly to Sp3-bound DNA through RbAp48, while mSin3A interacted with both HDACs. HDAC1 and HDAC2 were shown to potently repress the hLHR gene transcription, and mSin3A potentiated the inhibition mediated by HDAC1. Our studies have demonstrated that the HDAC-mSin3A complex has an important role in the regulation of hLHR gene transcription by interaction with Sp1/Sp3 and by region-specific changes in histone acetylation and polymerase II recruitment within the hLHR promoter. PMID:12091390

Zhang, Ying; Dufau, Maria L

2002-09-01

252

Histone Deacetylase Inhibitors in Malignant Pleural Mesothelioma  

PubMed Central

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

Paik, Paul K.; Krug, Lee M.

2014-01-01

253

Pharmaceutical composition containing a hypomethylating agent and a histone deacetylase inhibitor  

US Patent & Trademark Office Database

A pharmaceutical composition for induction therapy which has a hypomethylating agent and a histone deacetylase inhibitor ("HDAC inhibitor"); wherein the hypomethylating agent is a DNA and histone methylation inhibitor such as cladribine and the HDAC inhibitor is, for example, entinostat, panobinostat, vorinostat, and/or romedepsin; further wherein the hypomethylating agent and the HDAC inhibitor are combined in formulations for various administrations including e.g., a continuous delivery system such as a transdermal patch of at least one reservoir or a plurality of reservoirs, oral, a fixed-dose oral combination, intravenous, and combinations thereof. This pharmaceutical composition for induction therapy is used with a monoclonal antibody in the treatment of various cancers, sarcomas, and other malignancies.

2013-07-23

254

Histone/protein deacetylase inhibitors increase suppressive functions of human FOXP3+ Tregs1  

PubMed Central

Histone/protein deacetylases (HDACs) decrease histone and protein acetylation, typically leading to suppression of gene transcription and modulation of various protein functions. We found significant differences in expression of HDAC before and after stimulation of human T regulatory (Treg) and T effector cells, suggesting the potential for future selective targeting of Tregs with HDAC inhibitors (HDACi). Use of various HDACi small molecules enhanced, by up to 4.5-fold (average 2-fold), the suppressive functions of both freshly isolated and expanded human Tregs, consistent with our previous murine data. HDACi use increased Treg expression of CTLA-4, a key negative regulator of immune response, and we found a direct and significant correlation between CTLA-4 expression and Treg suppression. Hence, HDACi compounds are promising pharmacologic tools to increase Treg suppressive functions, and this action may potentially be of use in patients with autoimmunity or post-transplantation.

Akimova, Tatiana; Ge, Guanghui; Golovina, Tatiana; Mikheeva, Tatiana; Wang, Liqing; Riley, James L.; Hancock, Wayne W.

2010-01-01

255

Design and campaign synthesis of pyridine-based histone deacetylase inhibitors.  

PubMed

A lead benzamide, bearing a cyanopyridyl moiety (3), was identified as a potent and low molecular weight histone deacetylase (HDAC) inhibitor. Various replacements of the cyano group were explored at the C3-position, along with the exploration of solubility-enhancing groups at the C5-position. It was determined that cyano substitution at the C3-position of the pyridyl core, along with a methylazetidinyl substituent at the C5-position yielded optimal HDAC1 inhibition and anti-proliferative activity in HCT-116 cells. PMID:18378451

Andrews, David M; Gibson, Keith M; Graham, Mark A; Matusiak, Zbigniew S; Roberts, Craig A; Stokes, Elaine S E; Brady, Madeleine C; Chresta, Christine M

2008-04-15

256

Histone Deacetylase 11 Regulates Oligodendrocyte-Specific Gene Expression and Cell Development in OL-1 Oligodendroglia Cells  

PubMed Central

Both in vivo and in vitro studies indicate a correlation between reduced acetylation of histone core proteins and oligodendrocyte development. The nature of these histone modifications and the mechanisms mediating them remain undefined. To address these issues we utilized OL-1 cells, a rat non-transformed oligodendrocyte cell line, and primary oligodendrocyte cultures. We found that the acetylated histone H3 at lysine 9 and lysine 14 (H3K9/K14ac) is reduced in both the myelin basic protein (MBP) and proteolipid protein (PLP) genes of maturing oligodendroglial OL-1 cells, and furthermore, this temporally correlates with increases in MBP, PLP, and histone deacetylase (HDAC) 11 expression. Disruption of developmentally-regulated histone H3 deacetylation within the MBP and PLP genes by the HDAC inhibitor trichostatin A blunts MBP and PLP expression. With its increased expression, interaction of HDAC 11 with acetylated histone H3 and recruitment of HDAC 11 to the MBP and PLP genes markedly increases in maturing OL-1 cells. Moreover, suppressing HDAC 11 expression with small interfering RNA significantly: 1) increases H3K9/K14ac globally and within the MBP and PLP genes, 2) decreases MBP and PLP mRNA expression, and 3) blunts the morphological changes associated with oligodendrocyte development. Our data strongly support a specific role for HDAC 11 in histone deacetylation and in turn the regulation of oligodendrocyte-specific protein gene expression and oligodendrocyte development.

Liu, Hedi; Hu, Qichen; D'Ercole, A. Joseph; Ye, Ping

2008-01-01

257

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

258

Protein Kinases C and D Mediate Agonist-Dependent Cardiac Hypertrophy through Nuclear Export of Histone Deacetylase 5  

Microsoft Academic Search

A variety of stress signals stimulate cardiac myocytes to undergo hypertrophy. Persistent cardiac hypertro- phy is associated with elevated risk for the development of heart failure. Recently, we showed that class II histone deacetylases (HDACs) suppress cardiac hypertrophy and that stress signals neutralize this repressive function by triggering phosphorylation- and CRM1-dependent nuclear export of these chromatin-modifying enzymes. However, the identities

Rick B. Vega; Brooke C. Harrison; Eric Meadows; Charles R. Roberts; Philip J. Papst; Eric N. Olson; Timothy A. McKinsey

2004-01-01

259

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

260

Identification of type-specific anticancer histone deacetylase inhibitors: road to success.  

PubMed

Cancer is a serious and life-eliminating disease. Majority of anticancer agents are non-selective. Along with the cancerous cells they also target the normal ones. An important aspect is to hit the developing mechanism of the tumor, which is highlighted by in silico drug designing. On the basis of novel molecular targets, in silico (computational approach) drug discovery has emerged as today's need. Histone deacetylases are an important therapeutic target for many human cancers. The first and only approved (in 2006) histone deacetylase inhibitors (HDACIs) is Zolinza. Depending on the types of the histone deacetylase (HDAC) enzymes, discovery of type-specific inhibitors is important. With continued research and development, in near future HDACIs are likely to figure prominently in cancer treatment plans. This review presents the overview of HDACs, their role in cancer, their structural classes, activity, catalytic domain and the inhibitors of HDACs for cancer therapy. Also it helps in understanding the open directions in this area of research and highlights the importance of computational approaches in discovering specific drugs for cancer therapy. PMID:20401613

Noureen, Nighat; Rashid, Hamid; Kalsoom, Saima

2010-09-01

261

Endogenous Modulators and Pharmacological Inhibitors of Histone Deacetylases in Cancer Therapy  

PubMed Central

The class I histone deacetylases HDAC1 and HDAC2 belong to a family of 11 zinc-dependent human HDACs and are overexpressed in many cancers. Inhibitors of these HDACs now in clinical trials show activity against several types of cancers. This review is focuse on recent advances in both clinical and preclinical efforts to understand the basis for HDACi actions, with an emphasis on implications for rational combinations with conventional or other targeted agents. We will address new perspectives on the molecular mechanisms by which HDACs act and how these actions relate to cancer. We will also review new evidence demonstrating that HDACs are direct intracellular targets of the potent sphingolipid mediator sphingosine-1-phosphate (S1P), the first identified endogenous nuclear regulator of these enzymes, linking sphingolipid metabolism in the nucleus to remodeling of chromatin and epigenetic regulation of gene expression. Understanding how endogenous molecules regulate HDAC activity in vivo may facilitate the search for safer and more effective anti-cancer drugs capable of interfering with HDAC functions in a highly specific manner.

Spiegel, Sarah; Milstien, Sheldon; Grant, Steven

2012-01-01

262

CoREST is an integral component of the CoREST- human histone deacetylase complex.  

PubMed

Here we describe the components of a histone deacetylase (HDAC) complex that we term the CoREST-HDAC complex. CoREST-HDAC is composed of polypeptides distinct from previously characterized HDAC1/2-containing complexes such as the mSin3 and nucleosome remodeling and deacetylating (NRD, also named NURD, NuRD) complex. Interestingly, we do not observe RbAp46 and RbAp48 in this complex, although these proteins have been observed in all previously identified complexes and are thought to be part of an HDAC1/2 core. We identify the transcriptional corepressor CoREST and a protein with homology to polyamine oxidases as components of CoREST-HDAC. The HDAC1/2-interacting region of CoREST is mapped to a 179-aa region containing a SANT domain, a domain found in other HDAC1/2-interacting proteins such as NCoR, MTA1, and MTA2. Furthermore, we demonstrate that the corepressor function of CoREST depends on this region. Although CoREST initially was cloned as a corepressor to REST (RE1 silencing transcription factor/neural restrictive silencing factor), we find no evidence for the existence of the eight-zinc finger REST transcription factor as an interacting partner in this complex; however, we do find evidence for association of the putative oncogene ZNF 217 that contains eight zinc fingers. PMID:11171972

You, A; Tong, J K; Grozinger, C M; Schreiber, S L

2001-02-13

263

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

PubMed Central

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

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

2014-01-01

264

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

PubMed Central

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

Shaked, Maya; Weissmuller, Kathrin; Svoboda, Hanno; Hortschansky, Peter; Nishino, Norikazu; Wolfl, Stefan; Tucker, Kerry L.

2008-01-01

265

Histone deacetylase classes I and II regulate Kaposi's sarcoma-associated herpesvirus reactivation.  

PubMed

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

Shin, Hye Jin; DeCotiis, Jennifer; Giron, Mario; Palmeri, Diana; Lukac, David M

2014-01-01

266

Effects of histone deacetylase inhibitors on amygdaloid histone acetylation and neuropeptide Y expression: a role in anxiety-like and alcohol-drinking behaviours.  

PubMed

Recent studies have demonstrated the involvement of epigenetic mechanisms in psychiatric disorders, including alcoholism. Here, we investigated the effects of histone deacetylase (HDAC) inhibitor, trichostatin A (TSA) on amygdaloid HDAC-induced histone deacetylation and neuropeptide Y (NPY) expression and on anxiety-like and alcohol-drinking behaviours in alcohol-preferring (P) and -non-preferring (NP) rats. It was found that P rats displayed higher anxiety-like and alcohol-drinking behaviours, higher amygdaloid nuclear, but not cytosolic, HDAC activity, which was associated with increased HDAC2 protein levels and deficits in histone acetylation and NPY expression in the central (CeA) and medial nucleus of amygdala (MeA), as compared to NP rats. TSA treatment attenuated the anxiety-like and alcohol-drinking behaviours, with concomitant reductions in amygdaloid nuclear, but not cytosolic HDAC activity, and HDAC2, but not HDAC4, protein levels in the CeA and MeA of P rats, without effect in NP rats. TSA treatment also increased global histone acetylation (H3-K9 and H4-K8) and NPY expression in the CeA and MeA of P, but not in NP rats. Histone H3 acetylation within the NPY promoter was also innately lower in the amygdala of P rats compared with NP rats; which was normalized by TSA treatment. Voluntary ethanol intake in P, but not NP rats, produced anxiolytic effects and decreased the HDAC2 levels and increased histone acetylation in the CeA and MeA. These results suggest that higher HDAC2 expression-related deficits in histone acetylation may be involved in lower NPY expression in the amygdala of P rats, and operative in controlling anxiety-like and alcohol-drinking behaviours. PMID:24528596

Sakharkar, Amul J; Zhang, Huaibo; Tang, Lei; Baxstrom, Kathryn; Shi, Guangbin; Moonat, Sachin; Pandey, Subhash C

2014-08-01

267

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

PubMed Central

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

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

2014-01-01

268

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.

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

2013-01-01

269

A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression  

Microsoft Academic Search

The molecular mechanism for the anti-inflammatory action of theophylline is currently unknown, but low-dose theophylline is an effective add-on therapy to corticosteroids in controlling asthma. Corticosteroids act, at least in part, by recruitment of histone deacetylases (HDACs) to the site of active inflammatory gene transcription. They thereby inhibit the acetylation of core histones that is necessary for inflammatory gene transcription.

Kazuhiro Ito; Sam Lim; Gaetano Caramori; Borja Cosio; K. Fan Chung; Ian M. Adcock; Peter J. Barnes

2002-01-01

270

Identification of Histone Deacetylase 3 as a Biomarker for Tumor Recurrence Following Liver Transplantation in HBV-Associated Hepatocellular Carcinoma  

PubMed Central

Background Recent studies have shown that high expression levels of class I histone deacetylases (HDACs) correlate with malignant phenotype and poor prognosis in some human tumors. However, the expression patterns and prognostic role of class I HDAC isoforms in hepatocellular carcinoma (HCC) remain unclear. Methodology/Principal Findings The expression patterns and clinical significance of class I HDAC isoforms were assessed by immunohistochemistry in a cohort of 43 hepatitis B virus-associated HCC patients treated with liver transplantation. In addition, the effects of HDAC inhibition on HCC cell behavior were investigated by knockdown of the HDAC isoform with short interfering RNA. Class I HDACs were highly expressed in a subset of HCCs with positivity for HDAC1 in 51.2%, HDAC2 in 48.8%, and HDAC3 in 32.6% of cases. The expression levels of HDAC isoforms were significantly associated with the proliferation index of HCC. Kaplan-Meier curves showed that a high expression level of HDAC2 or HDAC3 implicated significantly reduced recurrence-free survival. Cox proportional hazards model analysis revealed HDAC3 overexpression was an unfavorable independent prognostic factor (P?=?0.002; HR 3.907). In vitro, inhibition of HDAC2 and HDAC3, but not HDAC1, suppressed proliferation and the invasiveness of liver cancer cells. Conclusions/Significance Our findings demonstrate that HDAC3 plays a significant role in regulating tumor cell proliferation and invasion, and it could be served as a candidate biomarker for predicting the recurrence of hepatitis B virus-associated HCC following liver transplantation and a potential therapeutic target.

Zhang, Feng; Xie, Hai-Yang; Feng, Xiao-Wen; Wu, Jian; Zheng, Shu-Sen

2010-01-01

271

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

272

Activation of p53 transcriptional activity by SMRT: a histone deacetylase 3-independent function of a transcriptional corepressor.  

PubMed

The silencing mediator of retinoic acid and thyroid hormone receptors (SMRT) is an established histone deacetylase 3 (HDAC3)-dependent transcriptional corepressor. Microarray analyses of MCF-7 cells transfected with control or SMRT small interfering RNA revealed SMRT regulation of genes involved in DNA damage responses, and the levels of the DNA damage marker ?H2AX as well as poly(ADP-ribose) polymerase cleavage were elevated in SMRT-depleted cells treated with doxorubicin. A number of these genes are established p53 targets. SMRT knockdown decreased the activity of two p53-dependent reporter genes as well as the expression of p53 target genes, such as CDKN1A (which encodes p21). SMRT bound directly to p53 and was recruited to p53 binding sites within the p21 promoter. Depletion of GPS2 and TBL1, components of the SMRT corepressor complex, but not histone deacetylase 3 (HDAC3) decreased p21-luciferase activity. p53 bound to the SMRT deacetylase activation domain (DAD), which mediates HDAC3 binding and activation, and HDAC3 could attenuate p53 binding to the DAD region of SMRT. Moreover, an HDAC3 binding-deficient SMRT DAD mutant coactivated p53 transcriptional activity. Collectively, these data highlight a biological role for SMRT in mediating DNA damage responses and suggest a model where p53 binding to the DAD limits HDAC3 interaction with this coregulator, thereby facilitating SMRT coactivation of p53-dependent gene expression. PMID:24449765

Adikesavan, Anbu Karani; Karmakar, Sudipan; Pardo, Patricia; Wang, Liguo; Liu, Shuang; Li, Wei; Smith, Carolyn L

2014-04-01

273

Nuclear Import of Histone Deacetylase 5 by Requisite Nuclear Localization Signal Phosphorylation*  

PubMed Central

Histone deacetylase 5 (HDAC5), a class IIa deacetylase, is a prominent regulator of cellular and epigenetic processes that underlie the progression of human disease, ranging from cardiac hypertrophy to cancer. Although it is established that phosphorylation mediates 14–3-3 protein binding and provides the essential link between HDAC5 nucleo-cytoplasmic shuttling and transcriptional repression, thus far only four phospho-acceptor sites have been functionally characterized. Here, using a combinatorial proteomics approach and phosphomutant screening, we present the first evidence that HDAC5 has at least 17 in vivo phosphorylation sites within functional domains, including Ser278 and Ser279 within the nuclear localization signal (NLS), Ser1108 within the nuclear export signal, and Ser755 in deacetylase domain. Global and targeted MS/MS analyses of NLS peptides demonstrated the presence of single (Ser278 and Ser279) and double (Ser278/Ser279) phosphorylations. The double S278/279A mutation showed reduced association with HDAC3, slightly decreased deacetylation activity, and significantly increased cytoplasmic localization compared with wild type HDAC5, whereas the S278A and S1108A phosphomutants were not altered. Live cell imaging revealed a deficiency in nuclear import of S278/279A HDAC5. Phosphomutant stable cell lines confirmed the cellular redistribution of NLS mutants and revealed a more pronounced cytoplasmic localization for the single S279A mutant. Proteomic analysis of immunoisolated S278/279A, S279A, and S259/498A mutants linked altered cellular localization to changes in protein interactions. S278/279A and S279A HDAC5 showed reduced association with the NCoR-HDAC3 nuclear corepressor complex as well as protein kinase D enzymes, which were potentiated in the S259/498A mutant. These results provide the first link between phosphorylation outside the known 14–3-3 sites and downstream changes in protein interactions. Together these studies identify Ser279 as a critical phosphorylation within the NLS involved in the nuclear import of HDAC5, providing a regulatory point in nucleo-cytoplasmic shuttling that may be conserved in other class IIa HDACs—HDAC4 and HDAC9.

Greco, Todd M.; Yu, Fang; Guise, Amanda J.; Cristea, Ileana M.

2011-01-01

274

Histone deacetylase inhibitors: molecular and biological activity as a premise to clinical application.  

PubMed

Epigenetic modifications are reversible chromatin rearrangements that in normal cells modulate gene expression, without changing DNA sequence. Alterations of this equilibrium, mainly affecting the two interdependent mechanisms of DNA methylation and histone acetylation, are frequently involved in the genesis of cancer. The histone code, regulating gene expression, is constituted by the combination of different acetylated lysine residues of histones. In neoplastic cells, the abundance of deacetylated histones is usually associated with DNA hypermethylation and gene silencing. Several compounds, known to have in vitro antineoplastic activity, have been eventually shown to act as histone deacetylase inhibitors. Thus, HDAC inhibitors have been successfully introduced in clinical trials as antitumour agents. They are classified according to their chemical structures and are endowed with different specificity and affinity for the HDACs of classes 1, 2, 4. Among HDAC inhibitors, the most potent are the hydroxamic acid derivatives, like SAHA, which has been recently approved for therapy of cutaneous T-cell lymphomas. Other classes of HDAC inhibitors are short chain fatty acids (SCFA), benzamides, epoxyketone and non-epoxyketone containing cyclic tetrapeptides, and hybrid molecules. SCFA, although widely used (especially valproic acid) and clinically efficacious, have weak HDAC inhibition constants. Benzamides, like MS-275, and cyclic peptides, like depsipeptide, have been studied in numerous clinical trials and demonstrated low toxicity and activity in solid and haematological neoplasms. HDAC inhibitors are also potent radiation sensitizers. Their future in oncology may thus be based on their activity as single agents and on their synergy with the hypomethylating drugs and with chemo- and radiotherapeutics. PMID:17504226

Santini, V; Gozzini, A; Ferrari, G

2007-05-01

275

Potential non-oncological applications of histone deacetylase inhibitors  

PubMed Central

Histone deacetylase inhibitors have emerged as a new class of anticancer therapeutic drugs. Their clinical utility in oncology stems from their intrinsic cytotoxic properties and combinatorial effects with other conventional cancer therapies. To date, the histone deacetylase inhibitors suberoylanilide hydroxamic acid (Vorinostat, Zolinza®) and depsipeptide (Romidepsin, Istodax®) have been approved by the US Food and Drug Administration for the treatment of refractory cutaneous T-cell lymphoma. Further, there are currently over 100 clinical trials involving the use of histone deacetylase inhibitors in a wide range of solid and hematological malignancies. The therapeutic potential of histone deacetylase inhibitors has also been investigated for numerous other diseases. For example, the cytotoxic properties of histone deacetylase inhibitors are currently being harnessed as a potential treatment for malaria, whereas the efficacy of these compounds for HIV relies on de-silencing latent virus. The anti-inflammatory properties of histone deacetylase inhibitors are the predominant mechanisms for other diseases, such as hepatitis, systemic lupus erythematosus and a wide range of neurodegenerative conditions. Additionally, histone deacetylase inhibitors have been shown to be efficacious in animal models of cardiac hypertrophy and asthma. Broad-spectrum histone deacetylase inhibitors are clinically available and have been used almost exclusively in preclinical systems to date. However, it is emerging that class- or isoform-specific compounds, which are becoming more readily available, may be more efficacious particularly for non-oncological applications. The aim of this review is to provide an overview of the effects and clinical potential of histone deacetylase inhibitors in various diseases. Apart from applications in oncology, the discussion is focused on the potential efficacy of histone deacetylase inhibitors for the treatment of neurodegenerative diseases, cardiac hypertrophy and asthma.

Ververis, Katherine; Karagiannis, Tom C

2011-01-01

276

Histone Deacetylase 1 Deficiency Impairs Differentiation and Electrophysiological Properties of Cardiomyocytes Derived from induced Pluripotent Cells  

PubMed Central

Epigenetic and chromatin modifications play particularly important roles in Embryonic and induced Pluripotent Stem cells (ES and iPS cells) allowing for the cells to both differentiate and dedifferentiate back to a pluripotent state. We analyzed how the loss of a key chromatin modifying enzyme, histone deacetylase 1(HDAC1), affects early and cardiovascular differentiation of both ES and iPS cells. We also investigated potential differences between these two cell types when differentiation is induced. Our data indicates an essential role for HDAC1 in deacetylating regulatory regions of key pluripotency-associated genes during early differentiation. Although HDAC1 functions primarily as a histone deacetylase, its loss also affects DNA methylation in ES and iPS cells both during pluripotency and differentiation. We show that HDAC1 plays a crucial, non-redundant role in cardiomyocyte differentiation and maturation. Our data also elucidates important differences between ES and iPS cells, when levels of this enzyme are reduced, that affect their ability to differentiate into functional cardiomyocytes. As varying levels of chromatin modifying enzymes are likely to exist in patient derived iPS cells, understanding the molecular circuitry of these enzymes in ES and iPS cells is critical for their potential use in cardiovascular therapeutic applications.

Hoxha, Eneda; Lambers, Erin; Xie, Hehuang; De Andrade, Alexandre; Krishnamurthy, Prasanna; Wasserstrom, John A.; Ramirez, Veronica; Thal, Melissa; Verma, Suresh K.; Soares, Marcelo B.; Kishore, Raj

2012-01-01

277

Histone deacetylase 7 regulates cell survival and TCR signaling in CD4/CD8 double-positive thymocytes.  

PubMed

CD4/CD8 double-positive thymocytes express the transcriptional repressor histone deacetylase (HDAC)7, a class IIa HDAC that is exported from the cell nucleus after TCR engagement. Through signal-dependent nuclear export, class IIa HDACs such as HDAC7 mediate signal-dependent changes in gene expression that are important to developmental fate decisions in multiple tissues. We report that HDAC7 is exported from the cell nucleus during positive selection in mouse thymocytes and that it regulates genes mediating the coupling between TCR engagement and downstream events that determine cell survival. Thymocytes lacking HDAC7 are inefficiently positively selected due to a severely shortened lifespan and exhibit a truncated repertoire of TCR J? segments. The expression of multiple important mediators and modulators of the response to TCR engagement is altered in HDAC7-deficient thymocytes, resulting in increased tonic MAPK activity that contributes to the observed loss of viability. Remarkably, the activity of protein kinase D, the kinase that mediates nuclear export of HDAC7 in response to TCR signaling, is also increased in HDAC7-deficient thymocytes, suggesting that HDAC7 nuclear export governs a self-sustaining autoexcitatory loop. These experiments add to the understanding of the life/death decision in thymic T cell development, define a novel function for class IIa HDACs, and point to a novel feed-forward mechanism whereby these molecules regulate their own state and mediate stable developmental transitions. PMID:21398603

Kasler, Herbert G; Young, Bryan D; Mottet, Denis; Lim, Hyung W; Collins, Amy M; Olson, Eric N; Verdin, Eric

2011-04-15

278

Toll-Like Signaling and the Cytokine IL-6 Regulate Histone Deacetylase Dependent Neuronal Survival  

PubMed Central

Histone deacetylase (HDAC) proteins have a role in promoting neuronal survival in vitro, but the mechanism underlying this function has not been identified. Here we provide evidence that components of the neuronal microenvironment, including non-neuronal cells and defined culture media, can mitigate midbrain neuronal cell death induced by HDAC inhibitor treatment. Using microarrays we further identified gene expression changes taking place in non-neuronal cells as a result of HDAC inhibition. This analysis demonstrated that HDAC inhibitor treatment results in the down-regulation of immunity related signaling factors, in particular the Toll-like receptors (TLR). TLR signaling is active in cultured midbrain cells, yet blocking TLR receptors is not sufficient to cause neuronal cell death. In contrast, selective activation of this pathway using TLR ligands can modestly block the effects of HDAC inhibition. Furthermore, we observed that the negative effects of HDAC inhibitor treatment on neuronal survival could be more substantially blocked by the cytokine Interleukin-6 (IL-6), which is a major downstream target of TLR signaling. These data suggest that HDACs function to promote neuronal survival by activating a TLR and IL-6 dependent pathway.

Forgione, Nicole; Tropepe, Vincent

2012-01-01

279

Histone deacetylase 6 regulates cytotoxic ?-synuclein accumulation through induction of the heat shock response.  

PubMed

Abnormal aggregation of ?-synuclein (?-syn) is central to the pathogenesis of Parkinson's disease (PD). Histone deacetylase 6 (HDAC6) was previously shown to control major cell response pathways to the cytotoxic ubiquitinated aggregates in some protein aggregation diseases. Whether it influences the aggregation process of ?-syn in PD models and its related mechanisms are not completely known. Here, we characterized the expression and function of HDAC6 in the ubiquitin-proteasome system impairment-induced PD model. Our results showed that HDAC6 inhibition further exacerbated the nigrostriatal dopamine neurodegeneration and upregulated ?-syn oligomers levels, whereas HDAC6 overexpression in vitro showed the opposite effects. More importantly, we provided evidence for the first time that HDAC6 regulating ?-syn oligomers levels were related to its ability to trigger the heat shock response in a heat shock protein 90-dependent manner. HDAC6 mediated the dissociation of heat shock protein 90-heat shock factor 1-containing complex, and the activation of heat shock factor 1, which led to the expression of major molecular chaperones to prevent the deleterious ?-syn aggregation. Thus, we propose that HDAC6 appears as a key modulator of cell protective response to the cytotoxic ?-syn aggregates and may serve as a potential target for therapy development in PD. PMID:24866403

Du, Yunlan; Wang, Fei; Zou, Jing; Le, Weidong; Dong, Qing; Wang, Zhiying; Shen, Fei; Yu, Ling; Li, Yansheng

2014-10-01

280

Targeting histone deacetylase activity in rheumatoid arthritis and asthma as prototypes of inflammatory disease: should we keep our HATs on?  

PubMed Central

Cellular activation, proliferation and survival in chronic inflammatory diseases is regulated not only by engagement of signal trans-duction pathways that modulate transcription factors required for these processes, but also by epigenetic regulation of transcription factor access to gene promoter regions. Histone acetyl trans-ferases coordinate the recruitment and activation of transcription factors with conformational changes in histones that allow gene promoter exposure. Histone deacetylases (HDACs) counteract histone acetyl transferase activity through the targeting of both histones as well as nonhistone signal transduction proteins important in inflammation. Numerous studies have indicated that depressed HDAC activity in patients with inflammatory airway diseases may contribute to local proinflammatory cytokine production and diminish patient responses to corticosteroid treatment. Recent observations that HDAC activity is depressed in rheumatoid arthritis patient synovial tissue have predicted that strategies restoring HDAC function may be therapeutic in this disease as well. Pharmacological inhibitors of HDAC activity, however, have demonstrated potent therapeutic effects in animal models of arthritis and other chronic inflammatory diseases. In the present review we assess and reconcile these outwardly paradoxical study results to provide a working model for how alterations in HDAC activity may contribute to pathology in rheumatoid arthritis, and highlight key questions to be answered in the preclinical evaluation of compounds modulating these enzymes.

Grabiec, Aleksander M; Tak, Paul P; Reedquist, Kris A

2008-01-01

281

The histone deacetylase-6 inhibitor tubacin directly inhibits de novo sphingolipid biosynthesis as an off-target effect.  

PubMed

Histone deacetylase 6 (HDAC6) controls acetylation of a number of cytosolic proteins, most prominently tubulin. Tubacin is a small molecule inhibitor of HDAC6 selected for its selective inhibition of HDAC6 relative to other histone deacetylases. For this reason it has become a useful pharmacological tool to discern the biological functions of HDAC6 in numerous cellular processes. The interest of this laboratory is in the function and regulation of sphingolipids, a family of lipids based on the sphingosine backbone. Sphingolipid biosynthesis is initiated by the rate limiting enzyme serine palmitoyltransferase (SPT). Sphingolipids have critical and diverse functions in cell survival, apoptosis, intra- and intercellular signaling, and in membrane structure. In the course of examining the role of HDAC6 in the regulation of sphingolipid biosynthesis we observed that tubacin strongly inhibited de novo synthesis whereas HDAC6 knockdown very moderately stimulated synthesis. We resolved these seemingly contradictory results by demonstrating that, surprisingly, tubacin is a direct inhibitor of SPT activity in permeabilized cells. Furthermore tubacin inhibits de novo sphingolipid synthesis in intact cells at doses commonly used to test HDAC6 function and does so in an HDAC6-independent manner. Niltubacin is a chemical analog of tubacin which lacks tubacin's HDAC6 activity, and so is often used as a control for off-target effects of tubacin. We find that niltubacin is inactive in the inhibition of sphingolipid biosynthesis, and so does not serve to distinguish the inhibitory effects of tubacin on HDAC6 from those on sphingolipid biosynthesis. These results indicate that caution should be used in the use of tubacin to study the role of HDAC6. PMID:24835950

Siow, Deanna; Wattenberg, Binks

2014-07-01

282

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 (Lys9-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

283

MAGE-A1 interacts with adaptor SKIP and the deacetylase HDAC1 to repress transcription  

PubMed Central

MAGE-A1 belongs to a family of 12 genes that are active in various types of tumors and silent in normal tissues except in male germ-line cells. The MAGE-encoded antigens recognized by T cells are highly tumor-specific targets for T cell-oriented cancer immunotherapy. The function of MAGE-A1 is currently unknown. To analyze it, we attempted to identify protein partners of MAGE-A1. Using yeast two-hybrid screening, we detected an interaction between MAGE-A1 and Ski Interacting Protein (SKIP). SKIP is a transcriptional regulator that connects DNA-binding proteins to proteins that either activate or repress transcription. We show that MAGE-A1 inhibits the activity of a SKIP-interacting transactivator, namely the intracellular part of Notch1. Deletion analysis indicated that this inhibition requires the binding of MAGE-A1 to SKIP. Moreover, MAGE-A1 was found to actively repress transcription by binding and recruiting histone deacetylase 1 (HDAC1). Our results indicate that by binding to SKIP and by recruiting HDACs, MAGE-A1 can act as a potent transcriptional repressor. MAGE-A1 could therefore participate in the setting of specific gene expression patterns for tumor cell growth or spermatogenesis.

Laduron, Sandra; Deplus, Rachel; Zhou, Sifang; Kholmanskikh, Olga; Godelaine, Daniele; De Smet, Charles; Hayward, S. Diane; Fuks, Francois; Boon, Thierry; De Plaen, Etienne

2004-01-01

284

Structure-based optimization of phenylbutyrate-derived histone deacetylase inhibitors.  

PubMed

Previously, we developed a strategy to develop a novel class of histone deacetylase (HDAC) inhibitors by tethering short-chain fatty acids with Zn(2+)-chelating motifs, which led to N-hydroxy-4-(4-phenylbutyryl-amino)benzamide (HTPB), a hydroxamate-tethered phenylbutyrate derivative with sub-micromolar potency in inhibiting HDAC activity and cancer cell proliferation. In this study, we carried out structure-based optimization of HTPB by using the framework generated by the structure of histone deacetylase-like protein (HDLP)-trichostatin A (TSA) complexes. Docking of HTPB into the HDLP binding domain suggested that the hydrophobic microenvironment encompassed by Phe-198 and Phe-200 could be exploited for structural optimization. This premise was corroborated by the greater potency of (S)-(+)-N-hydroxy-4-(3-methyl-2-phenylbutyrylamino)-benzamide [(S)-11] (IC(50) in HDAC inhibition, 16 nM), of which the isopropyl moiety was favorable in interacting with this hydrophobic motif. (S)-11 at concentrations as low as 0.1 microM was effective in causing histone hyperacetylation and p21(WAF/CIP1) overexpression and suppressing proliferation in cancer cells. PMID:16107152

Lu, Qiang; Wang, Da-Sheng; Chen, Chang-Shi; Hu, Yuan-Dong; Chen, Ching-Shih

2005-08-25

285

Functional analysis of histone deacetylase and its role in stress response, drug resistance and solid-state cultivation in Aspergillus oryzae.  

PubMed

In the eukaryotic cell, histone deacetylases (HDACs) play key roles in the regulation of fundamental cellular process such as development regulation, stress response, secondary metabolism and genome integrity. Here, we provide a comprehensive phenotypic analysis using HDAC disruptants in Aspergillus oryzae. Our study revealed that four HDACs, hdaA/Aohda1, hdaB/Aorpd3, hdaD/Aohos2 and hst4/AohstD were involved in stress response, cell wall synthesis and chromatin integrity in A. oryzae. Osmotic stress sensitivity of HDAC disruptants differed between plate cultures and liquid cultures, suggesting that HDACs adapt to the difference environmental conditions. Using a common A. oryzae fermentation medium, rice-koji, we also characterized HDACs related to growth and enzyme production to investigate which HDACs will be required for adaptation to environmental conditions and stress resistances. Because HDACs are widely conserved, our study has broad applications and may inform work with filamentous fungi and other eukaryote. PMID:24613105

Kawauchi, Moriyuki; Iwashita, Kazuhiro

2014-08-01

286

Histone deacetylase 3 modulates Tbx5 activity to regulate early cardiogenesis.  

PubMed

Congenital heart defects often result from improper differentiation of cardiac progenitor cells. Although transcription factors involved in cardiac progenitor cell differentiation have been described, the associated chromatin modifiers in this process remain largely unknown. Here we show that mouse embryos lacking the chromatin-modifying enzyme histone deacetylase 3 (Hdac3) in cardiac progenitor cells exhibit precocious cardiomyocyte differentiation, severe cardiac developmental defects, upregulation of Tbx5 target genes and embryonic lethality. Hdac3 physically interacts with Tbx5 and modulates its acetylation to repress Tbx5-dependent activation of cardiomyocyte lineage-specific genes. These findings reveal that Hdac3 plays a critical role in cardiac progenitor cells to regulate early cardiogenesis. PMID:24565863

Lewandowski, Sara L; Janardhan, Harish P; Smee, Kevin M; Bachman, Marcos; Sun, Zheng; Lazar, Mitchell A; Trivedi, Chinmay M

2014-07-15

287

Histone deacetylases and their inhibitors as potential therapeutic drugs for cholangiocarcinoma - cell line findings.  

PubMed

Histone deacetylation mediated by histone deacetylases (HDACs) has been reported as one of the epigenetic mechanisms associated with tumorigenesis. The poor responsiveness of anticancer drugs found with cholangiocarcinoma (CCA) leads to short survival rate. We aimed to investigate mRNA expression of HDACs class I and II, and the effect of HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA) and valproic acid (VPA), in CCA in vitro. Expression of HDACs was studied in CCA cell lines (M213, M214 and KKU-100) and an immortal cholangiocyte (MMNK1) by semi-quantitative reverse transcription-PCR. SAHA and VPA, as well as a classical chemotherapeutic drug 5-fluorouracil (5-FU) were used in this study. Cell proliferation was determined by sulforhodamine assay. IC50 and IC20 were then analyzed for each agent and cell line. Moreover, synergistic potential of VPA or SAHA in combination with 5-FU at subtoxic dose (IC20) of each agent was also evaluated. Statistic difference of HDACs expression or cell proliferation in each experimental condition was analyzed by Student's t-test. The result demonstrated that HDACs were expressed in all studied cell types. Both SAHA and VPA inhibited cell proliferation in a dose-dependent manner. Interestingly, KKU-100 which was less sensitive to classical chemotherapeutic 5-FU was highly sensitive to HDAC inhibitors. Simultaneous combination of subtoxic doses of HDAC inhibitors and 5-FU significantly inhibited cell proliferation in CCA cell lines compared to single agent treatment (P ? 0.01), while sequentially combined treatments were less effective. The present study showed inhibitory effects of HDACIs on cell proliferation in CCA cell lines, with synergistic antitumor potential demonstrated by simultaneous combination of VPA or SAHA with 5-FU, suggesting a novel alternative therapeutic strategy in effective treatment of CCA. PMID:23725164

Sriraksa, Ruethairat; Limpaiboon, Temduang

2013-01-01

288

Nuclear Receptor Corepressor-Histone Deacetylase 3 Governs Circadian Metabolic Physiology  

PubMed Central

Rhythmic changes in histone acetylation at circadian clock genes suggest that temporal modulation of gene expression is regulated by chromatin modifications1–3. Furthermore, recent studies demonstrate a critical relationship between circadian and metabolic physiology4–7. The Nuclear Receptor Co-Repressor 1 (NCoR) functions as an activating subunit for the chromatin modifying enzyme histone deacetylase 3 (HDAC3)8. Lack of NCoR is incompatible with life, and hence it is unknown whether NCoR, and particularly its regulation of HDAC3, is critical for adult mammalian physiology9. Here we show that specific, genetic disruption of the NCoR-HDAC3 interaction in mice causes aberrant regulation of clock genes and results in abnormal circadian behavior. These mice are also leaner and more insulin sensitive due to increased energy expenditure. Unexpectedly, loss of a functional NCoR-HDAC3 complex in vivo does not lead to sustained elevations of known catabolic genes, but rather significantly alters the oscillatory patterns of several metabolic genes, demonstrating that circadian regulation of metabolism is critical for normal energy balance. These findings indicate that activation of HDAC3 by NCoR is a nodal point in the epigenetic regulation of circadian and metabolic physiology.

Alenghat, Theresa; Meyers, Katherine; Mullican, Stannon E.; Leitner, Kirstin; Adeniji-Adele, Adetoun; Avila, Jacqueline; Bucan, Maja; Ahima, Rexford S.; Kaestner, Klaus H.; Lazar, Mitchell A.

2008-01-01

289

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

290

Histone deacetylase inhibitors: keeping momentum for neuromuscular and cardiovascular diseases treatment.  

PubMed

Histone deacetylases (HDACs) are enzymes with a pleiotropic range of intracellular localizations and actions. They are principally involved in the withdrawal of acetyl-groups from a large number of nuclear and cytoplasmic proteins including nuclear core histones as well as cytoskeletal proteins and metabolically relevant enzymes. Initial findings indicated that HDAC inhibitors (DIs) could be successfully applied in a variety of cancer treatment protocols as a consequence of their anti-proliferative and pro-apoptotic properties. Recent observations, however, enlightened the important therapeutic effects of DIs in experimental animal models for arthritis, neurodegenerative and neuromuscular disorders, heart ischemia, cardiac hypertrophy, heart failure and arrhythmias. A small number of clinical trials are now open or planned for the near future to verify the therapeutic properties of DIs in non-cancer-related diseases. This review summarizes some of the most important observations and concepts aroused by the most recent experimental application of DIs to neuromuscular and cardiac diseases. PMID:20227503

Colussi, Claudia; Illi, Barbara; Rosati, Jessica; Spallotta, Francesco; Farsetti, Antonella; Grasselli, Annalisa; Mai, Antonello; Capogrossi, Maurizio C; Gaetano, Carlo

2010-07-01

291

Histone deacetylase 1 and 2 are essential for normal T-cell development and genomic stability in mice.  

PubMed

Histone deacetylase 1 and 2 (HDAC1/2) regulate chromatin structure as the catalytic core of the Sin3A, NuRD and CoREST co-repressor complexes. To better understand the key pathways regulated by HDAC1/2 in the adaptive immune system and inform their exploitation as drug targets, we have generated mice with a T-cell specific deletion. Loss of either HDAC1 or HDAC2 alone has little effect, while dual inactivation results in a 5-fold reduction in thymocyte cellularity, accompanied by developmental arrest at the double-negative to double-positive transition. Transcriptome analysis revealed 892 misregulated genes in Hdac1/2 knock-out thymocytes, including down-regulation of LAT, Themis and Itk, key components of the T-cell receptor (TCR) signaling pathway. Down-regulation of these genes suggests a model in which HDAC1/2 deficiency results in defective propagation of TCR signaling, thus blocking development. Furthermore, mice with reduced HDAC1/2 activity (Hdac1 deleted and a single Hdac2 allele) develop a lethal pathology by 3-months of age, caused by neoplastic transformation of immature T cells in the thymus. Tumor cells become aneuploid, express increased levels of c-Myc and show elevated levels of the DNA damage marker, ?H2AX. These data demonstrate a crucial role for HDAC1/2 in T-cell development and the maintenance of genomic stability. PMID:23287868

Dovey, Oliver M; Foster, Charles T; Conte, Nathalie; Edwards, Sally A; Edwards, Jennifer M; Singh, Rajinder; Vassiliou, George; Bradley, Allan; Cowley, Shaun M

2013-02-21

292

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.

Ocker, Matthias

2010-01-01

293

Protein kinase D1 mediates class IIa histone deacetylase phosphorylation and nuclear extrusion in intestinal epithelial cells: role in mitogenic signaling.  

PubMed

We examined whether class IIa histone deacetylases (HDACs) play a role in mitogenic signaling mediated by protein kinase D1 (PKD1) in IEC-18 intestinal epithelial cells. Our results show that class IIa HDAC4, HDAC5, and HDAC7 are prominently expressed in these cells. Stimulation with ANG II, a potent mitogen for IEC-18 cells, induced a striking increase in phosphorylation of HDAC4 at Ser(246) and Ser(632), HDAC5 at Ser(259) and Ser(498), and HDAC7 at Ser(155). Treatment with the PKD family inhibitors kb NB 142-70 and CRT0066101 or small interfering RNA-mediated knockdown of PKD1 prevented ANG II-induced phosphorylation of HDAC4, HDAC5, and HDAC7. A variety of PKD1 activators in IEC-18 cells, including vasopressin, lysophosphatidic acid, and phorbol esters, also induced HDAC4, HDAC5, and HDAC7 phosphorylation. Using endogenously and ectopically expressed HDAC5, we show that PKD1-mediated phosphorylation of HDAC5 induces its nuclear extrusion into the cytoplasm. In contrast, HDAC5 with Ser(259) and Ser(498) mutated to Ala was localized to the nucleus in unstimulated and stimulated cells. Treatment of IEC-18 cells with specific inhibitors of class IIa HDACs, including MC1568 and TMP269, prevented cell cycle progression, DNA synthesis, and proliferation induced in response to G protein-coupled receptor/PKD1 activation. The PKD1-class IIa HDAC axis also functions in intestinal epithelial cells in vivo, since an increase in phosphorylation of HDAC4/5 and HDAC7 was demonstrated in lysates of crypt cells from PKD1 transgenic mice compared with matched nontransgenic littermates. Collectively, our results reveal a PKD1-class IIa HDAC axis in intestinal epithelial cells leading to mitogenic signaling. PMID:24647541

Sinnett-Smith, James; Ni, Yang; Wang, Jia; Ming, Ming; Young, Steven H; Rozengurt, Enrique

2014-05-15

294

An enzyme-coupled assay measuring acetate production for profiling histone deacetylase specificity.  

PubMed

Histone deacetylases catalyze the hydrolysis of an acetyl group from post-translationally modified acetyl-lysine residues in a wide variety of essential cellular proteins, including histones. Because these lysine modifications can alter the activity and properties of affected proteins, aberrant acetylation/deacetylation may contribute to disease states. Many fundamental questions regarding the substrate specificity and regulation of these enzymes have yet to be answered. Here, we optimize an enzyme-coupled assay to measure low micromolar concentrations of acetate, coupling acetate production to the formation of NADH (nicotinamide adenine dinucleotide, reduced form) that is measured by changes in either absorbance or fluorescence. Using this assay, we measured the steady-state kinetics of peptides representing the H4 histone tail and demonstrate that a C-terminally conjugated methylcoumarin enhances the catalytic efficiency of deacetylation catalyzed by cobalt(II)-bound histone deacetylase 8 [Co(II)-HDAC8] compared with peptide substrates containing a C-terminal carboxylate, amide, and tryptophan by 50-, 2.8-, and 2.3-fold, respectively. This assay can be adapted for a high-throughput screening format to identify HDAC substrates and inhibitors. PMID:24674948

Wolfson, Noah A; Pitcairn, Carol Ann; Sullivan, Eric D; Joseph, Caleb G; Fierke, Carol A

2014-07-01

295

The discovery and optimization of novel dual inhibitors of topoisomerase II and histone deacetylase.  

PubMed

A novel class of podophyllotoxin derivatives have been designed and synthesized based on the synergistic antitumor effects of topoisomerase II and histone deacetylase inhibitors. Their inhibitory activities towards histone deacetylases and Topo II and their cytotoxicities in cancer cell lines were evaluated. The aromatic capping group connection, linker length and zinc-binding group were systematically varied and preliminary conclusions regarding structure-activity relationships are discussed. Among all of the synthesized hybrid compounds, compound 24 d showed the most potent HDAC inhibitory activity at a low nanomolar level and exhibited powerful antiproliferative activity towards HCT116 colon carcinoma cells at a low micromolar level. Further exploration of this series led to the discovery of potent dual inhibitor 32, which exhibited the strongest in vitro cytotoxic activity. PMID:24095018

Zhang, Xuan; Bao, Bin; Yu, Xiuhua; Tong, Linjiang; Luo, Yu; Huang, Qingqing; Su, Mingbo; Sheng, Li; Li, Jia; Zhu, Hong; Yang, Bo; Zhang, Xiongwen; Chen, Yi; Lu, Wei

2013-11-15

296

Sonic Hedgehog-Induced Histone Deacetylase Activation Is Required for Cerebellar Granule Precursor Hyperplasia in Medulloblastoma  

PubMed Central

Medulloblastoma, the most common pediatric brain tumor, is thought to arise from deregulated proliferation of cerebellar granule precursor (CGP) cells. Sonic hedgehog (Shh) is the primary mitogen that regulates proliferation of CGP cells during the early stages of postnatal cerebellum development. Aberrant activation of Shh signaling during this time has been associated with hyperplasia of CGP cells and eventually may lead to the development of medulloblastoma. The molecular targets of Shh signaling involved in medulloblastoma formation are still not well-understood. Here, we show that Shh regulates sustained activation of histone deacetylases (HDACs) and that this activity is required for continued proliferation of CGP cells. Suppression of HDAC activity not only blocked the Shh-induced CGP proliferation in primary cell cultures, but also ameliorated aberrant CGP proliferation at the external germinal layer (EGL) in a medulloblastoma mouse model. Increased levels of mRNA and protein of several HDAC family members were found in medulloblastoma compared to wild type cerebellum suggesting that HDAC activity is required for the survival/progression of tumor cells. The identification of a role of HDACs in the early steps of medulloblastoma formation suggests there may be a therapeutic potential for HDAC inhibitors in this disease.

Lee, Seung Joon; Lindsey, Stephan; Graves, Bruce; Yoo, Soonmoon; Olson, James M.; Langhans, Sigrid A.

2013-01-01

297

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.

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

298

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

299

Discovery of Potent and Selective Histone Deacetylase Inhibitors via Focused Combinatorial Libraries of Cyclic ?3?-Tetrapeptides  

PubMed Central

Histone deacetylase (HDAC) inhibitors are powerful tools in understanding epigenetic regulation and have proven especially promising for the treatment of various cancers, but the discovery of potent, isoform-selective HDAC inhibitors has been a major challenge. We recently developed a cyclic ?3?-tetrapeptide scaffold for the preparation of HDAC inhibitors with novel selectivity profiles [Montero, A.; Beierle, J. M.; Olsen, C. A.; Ghadiri, M. R. J. Am. Chem. Soc. 2009, 131, 3033]. In this study, we elaborate this scaffold with respect to side chain diversity by synthesizing one-bead–one-compound combinatorial libraries of cyclic tetrapeptide analogs and applying two generations of these focused libraries to the discovery of potent HDAC ligands using a convenient screening platform. Our studies led to the first HDAC6–selective cyclic tetrapeptide analog, which extends the use of cyclic tetrapeptides to the class-II HDAC isoforms. These findings highlight the persistent potential of cyclic tetrapeptides as epigenetic modulators and possible anticancer-drug lead compounds.

Olsen, Christian A.; Ghadiri, M. Reza

2009-01-01

300

TIS7 interacts with the mammalian SIN3 histone deacetylase complex in epithelial cells  

PubMed Central

The mammalian SIN3 complex consists of histone deacetylases (HDAC1, HDAC2), several known proteins (SAP30, N-CoR) and as yet unidentified proteins. Here we show that the mouse tetradecanoyl phorbol acetate induced sequence 7 (TIS7) protein is a novel transcriptional co-repressor that can associate with the SIN3 complex. We have identified tis7 as a gene that is up-regulated upon loss of polarity in a mouse mammary gland epithelial cell line expressing an estrogen-inducible c-JunER fusion protein. In unpolarized cells, TIS7 protein levels increase and TIS7 translocates into the nucleus. Overexpression of tis7 causes loss of polarity and represses a set of genes, as revealed by cDNA microarray analysis. We have shown that TIS7 protein interacts with several proteins of the SIN3 complex (mSin3B, HDAC1, N-CoR and SAP30) by yeast two-hybrid screening and co-immunoprecipitations. TIS7 co-immunoprecipitated HDAC complex is enzymatically active and represses a GAL4-dependent reporter transcription. The transcriptional repression of endogenous genes by tis7 overexpression is HDAC dependent. Thus, we propose TIS7 as a transcriptional co-repressor affecting the expression of specific genes in a HDAC activity-dependent manner during cell fate decisions, e.g. scattering.

Vietor, Ilja; Vadivelu, Santhosh K.; Wick, Nikolaus; Hoffman, Robert; Cotten, Matt; Seiser, Christian; Fialka, Irene; Wunderlich, Winfried; Haase, Astrid; Korinkova, Gabriela; Brosch, Gerald; Huber, Lukas A.

2002-01-01

301

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

302

Role of the Sin3-histone deacetylase complex in growth regulation by the candidate tumor suppressor p33(ING1).  

PubMed

Sin3 is an evolutionarily conserved corepressor that exists in different complexes with the histone deacetylases HDAC1 and HDAC2. Sin3-HDAC complexes are believed to deacetylate nucleosomes in the vicinity of Sin3-regulated promoters, resulting in a repressed chromatin structure. We have previously found that a human Sin3-HDAC complex includes HDAC1 and HDAC2, the histone-binding proteins RbAp46 and RbAp48, and two novel polypeptides SAP30 and SAP18. SAP30 is a specific component of Sin3 complexes since it is absent in other HDAC1/2-containing complexes such as NuRD. SAP30 mediates interactions with different polypeptides providing specificity to Sin3 complexes. We have identified p33ING1b, a negative growth regulator involved in the p53 pathway, as a SAP30-associated protein. Two distinct Sin3-p33ING1b-containing complexes were isolated, one of which associates with the subunits of the Brg1-based Swi/Snf chromatin remodeling complex. The N terminus of p33ING1b, which is divergent among a family of ING1 polypeptides, associates with the Sin3 complex through direct interaction with SAP30. The N-terminal domain of p33 is present in several uncharacterized human proteins. We show that overexpression of p33ING1b suppresses cell growth in a manner dependent on the intact Sin3-HDAC-interacting domain. PMID:11784859

Kuzmichev, A; Zhang, Y; Erdjument-Bromage, H; Tempst, P; Reinberg, D

2002-02-01

303

Activation of tissue transglutaminase transcription by histone deacetylase inhibition as a therapeutic approach for Myc oncogenesis  

PubMed Central

Histone deacetylase (HDAC) inhibitors reactivate tumor suppressor gene transcription; induce cancer cell differentiation, growth arrest, and programmed cell death; and are among the most promising new classes of anticancer drugs. Myc oncoproteins can block cell differentiation and promote cell proliferation and malignant transformation, in some cases by modulating target gene transcription. Here, we show that tissue transglutaminase (TG2) was commonly reactivated by HDAC inhibitors in neuroblastoma and breast cancer cells but not normal cells and contributed to HDAC inhibitor-induced growth arrest. TG2 was the gene most significantly repressed by N-Myc in neuroblastoma cells in a cDNA microarray analysis and was commonly repressed by N-Myc in neuroblastoma cells and c-Myc in breast cancer cells. Repression of TG2 expression by N-Myc in neuroblastoma cells was necessary for the inhibitory effect of N-Myc on neuroblastoma cell differentiation. Dual step cross-linking chromatin immunoprecipitation and protein coimmunoprecipitation assays showed that N-Myc acted as a transrepressor by recruiting the HDAC1 protein to an Sp1-binding site in the TG2 core promoter in a manner distinct from it's action as a transactivator at E-Box binding sites. HDAC inhibitor treatment blocked the N-Myc-mediated HDAC1 recruitment and TG2 repression in vitro. In neuroblastoma-bearing N-Myc transgenic mice, HDAC inhibitor treatment induced TG2 expression and demonstrated marked antitumor activity in vivo. Taken together, our data indicate the critical roles of HDAC1 and TG2 in Myc-induced oncogenesis and have significant implications for the use of HDAC inhibitor therapy in Myc-driven oncogenesis.

Liu, Tao; Tee, Andrew E. L.; Porro, Antonio; Smith, Stewart A.; Dwarte, Tanya; Liu, Pei Yan; Iraci, Nunzio; Sekyere, Eric; Haber, Michelle; Norris, Murray D.; Diolaiti, Daniel; Della Valle, Giuliano; Perini, Giovanni; Marshall, Glenn M.

2007-01-01

304

Histone deacetylase inhibitors stimulate dedifferentiation of human breast cancer cells through WNT/?-catenin signaling.  

PubMed

Recent studies have shown that differentiated cancer cells can dedifferentiate into cancer stem cells (CSCs) although to date no studies have reported whether this transition is influenced by systemic anti-cancer agents. Valproic acid (VA) is a histone deacetylase (HDAC) inhibitor that promotes self-renewal and expansion of hematopoietic stem cells and facilitates the generation of induced pluripotent stem cells from somatic cells and is currently being investigated in breast cancer clinical trials. We hypothesized that HDAC inhibitors reprogram differentiated cancer cells toward the more resistant stem cell-like state. Two highly aggressive breast cancer cell lines, SUM159 and MDA-231, were sorted based on aldehyde dehydrogenase (ALDH) activity and subsequently ALDH-negative and ALDH-positive cells were treated with one of two known HDAC inhibitors, VA or suberoylanilide hydroxamic acid. In addition, primary tumor cells from patients with metastatic breast cancer were evaluated for ALDH activity following treatment with HDAC inhibitors. We demonstrate that single-cell-sorted ALDH-negative cells spontaneously generated ALDH-positive cells in vitro. Treatment of ALDH-negative cells with HDAC inhibitors promoted the expansion of ALDH-positive cells and increased mammosphere-forming efficiency. Most importantly, it significantly increased the tumor-initiating capacity of ALDH-negative cells in limiting dilution outgrowth assays. Moreover, while HDAC inhibitors upregulated ?-catenin expression and significantly increased WNT reporter activity, a TCF4 dominant negative construct abolished HDAC-inhibitor-induced expansion of CSCs. These results demonstrate that HDAC inhibitors promote the expansion of breast CSCs through dedifferentiation and have important clinical implications for the use of HDAC inhibitors in the treatment of cancer. PMID:22961641

Debeb, Bisrat G; Lacerda, Lara; Xu, Wei; Larson, Richard; Solley, Travis; Atkinson, Rachel; Sulman, Erik P; Ueno, Naoto T; Krishnamurthy, Savitri; Reuben, James M; Buchholz, Thomas A; Woodward, Wendy A

2012-11-01

305

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

SciTech Connect

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

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

2010-08-23

306

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

PubMed

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

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

2014-07-01

307

An active site tyrosine residue is essential for amidohydrolase but not for esterase activity of a class 2 histone deacetylase-like bacterial enzyme  

PubMed Central

HDACs (histone deacetylases) are considered to be among the most important enzymes that regulate gene expression in eukaryotic cells acting through deacetylation of ?-acetyl-lysine residues within the N-terminal tail of core histones. In addition, both eukaryotic HDACs as well as their bacterial counterparts were reported to also act on non-histone targets. However, we are still far from a comprehensive understanding of the biological activities of this ancient class of enzymes. In the present paper, we studied in more detail the esterase activity of HDACs, focussing on the HDAH (histone deacetylase-like amidohydrolase) from Bordetella/Alcaligenes strain FB188. This enzyme was classified as a class 2 HDAC based on sequence comparison as well as functional data. Using chromogenic and fluorogenic ester substrates we show that HDACs such as FB188 HDAH indeed have esterase activity that is comparable with those of known esterases. Similar results were obtained for human HDAC1, 3 and 8. Standard HDAC inhibitors were able to block both activities with similar IC50 values. Interestingly, HDAC inhibitors such as suberoylanilide hydroxamic acid (SAHA) also showed inhibitory activity against porcine liver esterase and Pseudomonas fluorescens lipase. The esterase and the amidohydrolase activity of FB188 HDAH both appear to have the same substrate specificity concerning the acyl moiety. Interestingly, a Y312F mutation in the active site of HDAH obstructed amidohydrolase activity but significantly improved esterase activity, indicating subtle differences in the mechanism of both catalytic activities. Our results suggest that, in principle, HDACs may have other biological roles besides acting as protein deacetylases. Furthermore, data on HDAC inhibitors affecting known esterases indicate that these molecules, which are currently among the most promising drug candidates in cancer therapy, may have a broader target profile requiring further exploration.

Moreth, Kristin; Riester, Daniel; Hildmann, Christian; Hempel, Rene; Wegener, Dennis; Schober, Andreas; Schwienhorst, Andreas

2006-01-01

308

Analysis of histone acetyltransferase and histone deacetylase families of Arabidopsis thaliana suggests functional diversification of chromatin modification among multicellular eukaryotes  

PubMed Central

Sequence similarity and profile searching tools were used to analyze the genome sequences of Arabidopsis thaliana, Saccharomyces cerevisiae, Schizosaccharomyces pombe, Caenorhabditis elegans and Drosophila melanogaster for genes encoding three families of histone deacetylase (HDAC) proteins and three families of histone acetyltransferase (HAT) proteins. Plants, animals and fungi were found to have a single member of each of three subfamilies of the GNAT family of HATs, suggesting conservation of these functions. However, major differences were found with respect to sizes of gene families and multi-domain protein structures within other families of HATs and HDACs, indicating substantial evolutionary diversification. Phylogenetic analysis identified a new class of HDACs within the RPD3/HDA1 family that is represented only in plants and animals. A similar analysis of the plant-specific HD2 family of HDACs suggests a duplication event early in dicot evolution, followed by further diversification in the lineage leading to Arabidopsis. Of three major classes of SIR2-type HDACs that are found in animals, fungi have representatives only in one class, whereas plants have representatives only in the other two. Plants possess five CREB-binding protein (CBP)-type HATs compared with one to two in animals and none in fungi. Domain and phylogenetic analyses of the CBP family proteins showed that this family has evolved three distinct types of CBPs in plants. The domain architecture of CBP and TAFII250 families of HATs show significant differences between plants and animals, most notably with respect to bromodomain occurrence and their number. Bromodomain-containing proteins in Arabidopsis differ strikingly from animal bromodomain proteins with respect to the numbers of bromodomains and the other types of domains that are present. The substantial diversification of HATs and HDACs that has occurred since the divergence of plants, animals and fungi suggests a surprising degree of evolutionary plasticity and functional diversification in these core chromatin components.

Pandey, Ritu; Muller, Andreas; Napoli, Carolyn A.; Selinger, David A.; Pikaard, Craig S.; Richards, Eric J.; Bender, Judith; Mount, David W.; Jorgensen, Richard A.

2002-01-01

309

Histone deacetylase inhibitors upregulate Rap1GAP and inhibit Rap activity in thyroid tumor cells.  

PubMed

Increases in Rap activity have been associated with tumor progression. Although activating mutations in Rap have not been described, downregulation of Rap1GAP is frequent in human tumors including thyroid carcinomas. In this study, we explored whether endogenous Rap1GAP expression could be restored to thyroid tumor cells. The effects of deacetylase inhibitors and a demethylating agent, individually and in combination, were examined in four differentiated and six anaplastic thyroid carcinoma (ATC) cell lines. Treatment with the structurally distinct histone deacetylase (HDAC) inhibitors, sodium butyrate and trichostatin A, increased Rap1GAP expression in all the differentiated thyroid carcinoma cell lines and in four of the six ATC cell lines. The demethylating agent, 5-aza-deoxycytidine, restored Rap1GAP expression in one anaplastic cell line and enhanced the effects of HDAC inhibitors in a second anaplastic cell line. Western blotting indicated that Rap2 was highly expressed in human thyroid cancer cells. Importantly, treatment with HDAC inhibitors impaired Rap2 activity in both differentiated and anaplastic tumor cell lines. The mechanism through which Rap activity is repressed appears to entail effects on the expression of multiple Rap regulators, including RapGEFs and RapGAPs. These results suggest that HDAC inhibitors may provide a tractable approach to impair Rap activity in human tumor cells. PMID:21367844

Dong, Xiaoyun; Korch, Christopher; Meinkoth, Judy L

2011-06-01

310

Histone deacetylase inhibitors upregulate Rap1GAP and inhibit Rap activity in thyroid tumor cells  

PubMed Central

Increases in Rap activity have been associated with tumor progression. Although activating mutations in Rap have not been described, downregulation of Rap1GAP is frequent in human tumors including thyroid carcinomas. In this study, we explored whether endogenous Rap1GAP expression could be restored to thyroid tumor cells. The effects of deacetylase inhibitors and a demethylating agent, individually and in combination, were examined in four differentiated and six anaplastic thyroid carcinoma (ATC) cell lines. Treatment with the structurally distinct histone deacetylase (HDAC) inhibitors, sodium butyrate and trichostatin A, increased Rap1GAP expression in all the differentiated thyroid carcinoma cell lines and in four of the six ATC cell lines. The demethylating agent, 5-aza-deoxycytidine, restored Rap1GAP expression in one anaplastic cell line and enhanced the effects of HDAC inhibitors in a second anaplastic cell line. Western blotting indicated that Rap2 was highly expressed in human thyroid cancer cells. Importantly, treatment with HDAC inhibitors impaired Rap2 activity in both differentiated and anaplastic tumor cell lines. The mechanism through which Rap activity is repressed appears to entail effects on the expression of multiple Rap regulators, including RapGEFs and RapGAPs. These results suggest that HDAC inhibitors may provide a tractable approach to impair Rap activity in human tumor cells.

Dong, Xiaoyun; Korch, Christopher; Meinkoth, Judy L

2012-01-01

311

Rationale for the use of histone deacetylase inhibitors as a dual therapeutic modality in multiple sclerosis.  

PubMed

Major recent advances in the field of chromatin remodeling have dramatically changed our understanding of the ways in which genes are regulated. Epigenetic regulators such as histone deacetylases (HDACs) and histone acetyltransferases (HATs) are increasingly being implicated as direct or indirect components in the regulation of expression of neuronal, immune and other tissue specific genes. HDACs and HATs have been shown to play important roles in cell growth, cell cycle control, development, differentiation and survival. Mutations in genes that encode HDAC-binding proteins cause neurological disorders, such as MeCP2 mutations in Rett's syndrome. Mutations of CBP, a gene with HAT function, cause the mental retardation-associated Rubinstein-Taybi syndrome. Recently, HDAC inhibitors have been found to ameliorate progression of the spinal muscular atrophy (SMA) motor neuron disease and the Huntington disease mouse models. The neuroprotective role of HDAC inhibitors seems to extend to other diseases that share mechanisms of oxidative stress, inflammation and neuronal cell apoptosis. HDAC inhibitors also have widespread modulatory effects on gene expression within the immune system and have been used successfully in the lupus and rheumatoid arthritis autoimmune disease models. Recently, we demonstrated the efficacy of the HDAC inhibitor Trichostatin A in ameliorating disease in the multiple sclerosis (MS) animal model, experimental autoimmune encephalomyelitis (EAE). In this review we describe the current literature surrounding these inhibitors and propose a rationale for harnessing both their neuroprotective and anti-inflammatory effects to treat MS, an autoimmune, demyelinating and degenerative disease of the human central nervous system (CNS). PMID:17998807

Gray, Steven G; Dangond, Fernando

2006-01-01

312

Histone Deacetylase Inhibitors Equipped with Estrogen Receptor Modulation Activity  

PubMed Central

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

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

2013-01-01

313

Histone Deacetylase Inhibition and Dietary Short-Chain Fatty Acids  

PubMed Central

Changes in diet can also have dramatic effects on the composition of gut microbiota. Commensal bacteria of the gastrointestinal tract are critical regulators of health and disease by protecting against pathogen encounter whilst also maintaining immune tolerance to certain allergens. Moreover, consumption of fibre and vegetables typical of a non-Western diet generates substantial quantities of short-chain fatty acids (SCFAs) which have potent anti-inflammatory properties. Dietary interventions such as probiotic supplementation have been investigated for their pleiotropic effects on microbiota composition and immune function. Probiotics may restore intestinal dysbiosis and improve clinical disease through elevated SCFA levels in the intestine. Although the precise mechanisms by which such dietary factors mediate these effects, SCFA metabolites such as butyrate also function as histone deacetylase inhibitors (HDACi), that can act on the epigenome through chromatin remodeling changes. The aim of this review is to provide an overview of HDAC enzymes and to discuss the biological effects of HDACi. Further, we discuss the important relationship between diet and the balance between health and disease and how novel dietary interventions such as probiotics could be alternative approach for the prevention and/or treatment of chronic inflammatory disease through modulation of the intestinal microbiome.

Licciardi, Paul V.; Ververis, Katherine; Karagiannis, Tom C.

2011-01-01

314

Liposomes loaded with histone deacetylase inhibitors for breast cancer therapy.  

PubMed

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

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

2010-09-15

315

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.

Ziesche, Elisabeth; Kettner-Buhrow, Daniela; Weber, Axel; Wittwer, Tobias; Jurida, Liane; Soelch, Johanna; Muller, 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

316

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

317

Histone Deacetylase 6 and Heat Shock Protein 90 Control the Functions of Foxp3+ T-Regulatory Cells?  

PubMed Central

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.

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.

2011-01-01

318

Histone Deacetylase Inhibitor Depsipeptide (FK228) Induces Apoptosis in Leukemic Cells by Facilitating Mitochondrial Translocation of Bax, Which Is Enhanced by the Proteasome Inhibitor Bortezomib  

Microsoft Academic Search

Histone deacetylase (HDAC) inhibitors are promising candidates for molecular-targeted therapy for leukemia. In this study, we investigated the mechanisms of cytotoxic effects of depsipeptide (FK228), one of the most effective HDAC inhibitors against leukemia, using human myeloid leukemic cell lines HL-60 and K562. We found that FK228 activated caspase-9 and a subsequent caspase cascade by perturbing the mitochondrial membrane to

Krittaya Sutheesophon; Yukiko Kobayashi; Masa-aki Takatoku; Keiya Ozawa; Yasuhiko Kano; Hideshi Ishii; Yusuke Furukawa

2006-01-01

319

Pharmacokinetics and tissue distribution of Kendine 91, a novel histone deacetylase inhibitor, in mice  

Microsoft Academic Search

Purpose  The present investigation was undertaken to characterize the pharmacokinetics and oral bioavailability of Kendine 91 in mice\\u000a and to compare it with other HDAC (histone deacetylases) inhibitors.\\u000a \\u000a \\u000a \\u000a Methods  After administration of a single intravenous dose (10 mg\\/kg) or a single oral dose (50 mg\\/kg) blood and tissues samples were\\u000a collected and analysed by HPLC\\/MS\\/MS.\\u000a \\u000a \\u000a \\u000a Results  Elimination half-life was higher than that of SAHA (5.87

Dorleta Otaegui; Alicia Rodríguez-Gascón; Aizpea Zubia; Fernando P. Cossío; José Luis Pedraz

2009-01-01

320

Histone deacetylases are critical regulators of the renin-angiotensin system during ureteric bud branching morphogenesis.  

PubMed

Mutations in the genes encoding components of the renin-angiotensin system (RAS) in mice or humans cause congenital abnormalities of the kidney and urinary tract. We hypothesized that absence of angiotensin (Ang) II in angiotensinogen (AGT)-deficient mice leads to defects in ureteric bud (UB) branching and that RAS genes are critically dependent on histone deacetylase (HDAC) activity. The number of UB tips was lower in AGT-/- compared with AGT+/+ embryonic (E) day E13.5 metanephroi (24+/-1.5 versus 36+/-3.7, p<0.05). Real-time RT-PCR demonstrated that pharmacological inhibition of HDAC activity with Scriptaid increases AGT, renin, angiotensin-converting enzyme (ACE), and AT1 receptor (AT1R) mRNA levels in E12.5 mouse metanephroi and early mesenchymal (MK3) cells. Furthermore, Scriptaid enhanced Ang II induced decrease in Sprouty (Spry) 1 gene expression in cultured UB cells. Treatment of intact E12.5 mouse metanephroi grown ex vivo with Ang II (10(-5) M, 24 h) increased HDAC-1 and decreased total acetylated histone H3 protein levels. These findings indicate that lack of endogenous Ang II in AGT-deficient mice inhibits UB branching. We conclude that intact RAS is critical in structural integrity of the renal collecting system and that UB morphogenetic program genes, such as AGT, renin, ACE, AT1R, or Spry1, are epigenetically controlled via HDACs. PMID:20496471

Song, Renfang; Van Buren, Thomas; Yosypiv, Ihor V

2010-06-01

321

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.

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

2013-01-01

322

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

PubMed Central

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 core histones. Very recently, we showed that HdaA, a member of the Saccharomyces cerevisiae HDA1-type histone deacetylases, is a substantial contributor to total HDAC activity in the filamentous fungus Aspergillus nidulans. Now we demonstrate that deletion of the hdaA gene indeed results in the loss of the main activity peak and in a dramatic reduction of total HDAC activity. In contrast to its orthologs in yeast and higher eukaryotes, HdaA has strong intrinsic activity as a protein monomer when expressed as a recombinant protein in a prokaryotic expression system. In vivo, HdaA is involved in the regulation of enzymes which are of vital importance for the cellular antioxidant response in A. nidulans. Consequently, ?hdaA strains exhibit significantly reduced growth on substrates whose catabolism generates molecules responsible for oxidative stress conditions in the fungus. Our analysis revealed that reduced expression of the fungal catalase CatB is jointly responsible for the significant growth reduction of the hdaA mutant strains.

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

2005-01-01

323

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.

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

2012-01-01

324

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

Microsoft Academic Search

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

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

2004-01-01

325

Aberrant Recruitment of the Nuclear Receptor Corepressor Histone Deacetylase Complex by the Acute Myeloid Leukemia Fusion Partner ETO  

Microsoft Academic Search

Nuclear receptor corepressor (CoR)-histone deacetylase (HDAC) complex recruitment is indispensable for the biological activities of the retinoic acid receptor fusion proteins of acute promyelocytic leukemias. We report here that ETO (eight-twenty-one or MTG8), which is fused to the acute myelogenous leukemia 1 (AML1) transcription factor in t(8;21) AML, interacts via its zinc finger region with a conserved domain of the

VANIA GELMETTI; JINSONG ZHANG; MIRCO FANELLI; SAVERIO MINUCCI; PIER GIUSEPPE PELICCI; MITCHELL A. LAZAR

1998-01-01

326

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

327

Stable histone deacetylase complexes distinguished by the presence of SANT domain proteins CoREST/kiaa0071 and Mta-L1.  

PubMed

Human histone deacetylases I (HDAC1) and II (HDAC2) are homologous proteins (84% identity) that catalyze release of acetyl groups from modified N-terminal lysines of core histones. Histone deacetylation is correlated with both transient and persistent states of transcriptional inactivity (i.e. silencing) in many eukaryotes. In this study, we analyzed complexes containing HDAC1 and HDAC2 to identify the proteins most stably associated with these deacetylases. Complex cI (9.5 S) contained transcriptional corepressor CoREST/kiaa0071 and a protein homologous to FAD-dependent oxidoreductases, kiaa0601. Complex cII (15 S) contained >/=15 proteins, including CHD3/4 (Mi-2), Mta-L1, RbAp48/46, and MBD3, characteristic of vertebrate nucleosome-remodeling complexes. Under native conditions, cI and cII may contain HDAC1, HDAC2 or both; these can be dissociated to cI and cII core complexes containing only HDAC1 or HDAC2. The (m)CpG-binding protein MBD2 was associated only with the HDAC1 cII core complex. A model is proposed in which HDAC1 core complexes can be targeted to methylated DNA via MBD2 with recruitment of HDAC2 occurring through formation of HDAC1/2 cII dimers. We note that the cI component CoREST/kiaa0071 and the cII component Mta-L1 share a region of homology that includes a SANT domain; this domain may play a role in complex assembly. PMID:11102443

Humphrey, G W; Wang, Y; Russanova, V R; Hirai, T; Qin, J; Nakatani, Y; Howard, B H

2001-03-01

328

Effects of histone deacetylase inhibitor oxamflatin on in vitro porcine somatic cell nuclear transfer embryos.  

PubMed

Abstract Low cloning efficiency is considered to be caused by the incomplete or aberrant epigenetic reprogramming of differentiated donor cells in somatic cell nuclear transfer (SCNT) embryos. Oxamflatin, a novel class of histone deacetylase inhibitor (HDACi), has been found to improve the in vitro and full-term developmental potential of SCNT embryos. In the present study, we studied the effects of oxamflatin treatment on in vitro porcine SCNT embryos. Our results indicated that the rate of in vitro blastocyst formation of SCNT embryos treated with 1??M oxamflatin for 15?h postactivation was significantly higher than all other treatments. Treatment of oxamflatin decreased the relative histone deacetylase (HDAC) activity in cloned embryos and resulted in hyperacetylation levels of histone H3 at lysine 9 (AcH3K9) and histone H4 at lysine 5 (AcH4K5) at pronuclear, two-cell, and four-cell stages partly through downregulating HDAC1. The suppression of HDAC6 through oxamflatin increased the nonhistone acetylation level of ?-tubulin during the mitotic cell cycle of early SCNT embryos. In addition, we demonstrated that oxamflatin downregulated DNA methyltransferase 1 (DNMT1) expression and global DNA methylation level (5-methylcytosine) in two-cell-stage porcine SCNT embryos. The pluripotency-related gene POU5F1 was found to be upregulated in the oxamflatin-treated group with a decreased DNA methylation tendency in its promoter regions. Treatment of oxamflatin did not change the locus-specific DNA methylation levels of Sus scrofa heterochromatic satellite DNA sequences at the blastocyst stage. Meanwhile, our findings suggest that treatment with HDACi may contribute to maintaining the stable status of cytoskeleton-associated elements, such as acetylated ?-tubulin, which may be the crucial determinants of donor nuclear reprogramming in early SCNT embryos. In summary, oxamflatin treatment improves the developmental potential of porcine SCNT embryos in vitro. PMID:24960409

Hou, Liming; Ma, Fanhua; Yang, Jinzeng; Riaz, Hasan; Wang, Yongliang; Wu, Wangjun; Xia, Xiaoliang; Ma, Zhiyuan; Zhou, Ying; Zhang, Lin; Ying, Wenqin; Xu, Dequan; Zuo, Bo; Ren, Zhuqing; Xiong, Yuanzhu

2014-08-01

329

Notch1 mediates growth suppression of papillary and follicular thyroid cancer cells by histone deacetylase inhibitors.  

PubMed

Notch1 is a multifunctional transmembrane receptor that regulates cellular differentiation, development, proliferation, and survival in a variety of contexts. We have previously shown that Notch1 may function as a tumor suppressor and that histone deacetylase (HDAC) inhibitors can induce Notch1 expression in some endocrine cancers. Here, we showed that although there was minimal Notch1 expression in follicular thyroid cancer FTC236 and papillary thyroid cancer DRO cells, transfection of constitutive Notch1 plasmid into these cells led to growth inhibition, down-regulation of cyclin D1, and up-regulation of p21. Treatment of FTC236 cells with HDAC inhibitors valproic acid (1-4 mmol/L) or suberoyl bishydroxamic acid (10-30 micromol/L) induced functional Notch1 protein expression and suppressed cell growth in a dose-dependent manner. Notch1 siRNA interference blocked the antiproliferative effect of HDAC inhibitors. Western blot analysis revealed the reduction of cyclin D1 and the increase of p21 in HDAC inhibitor-treated cells. These results indicate that HDAC inhibitors activate Notch1 signaling in thyroid cancer cells and lead to the suppression of proliferation by cell cycle arrest. Our findings provide the first documentation of the role of Notch1 signaling as a tumor suppressor in DRO and FTC236 cells, suggesting that Notch1 activation may be a potential therapeutic target for papillary and follicular thyroid cancers. PMID:19190121

Xiao, Xueming; Ning, Li; Chen, Herbert

2009-02-01

330

Nuclear export of histone deacetylase 7 during thymic selection is required for immune self-tolerance.  

PubMed

Histone deacetylase 7 (HDAC7) is a T-cell receptor (TCR) signal-dependent regulator of differentiation that is highly expressed in CD4/CD8 double-positive (DP) thymocytes. Here, we examine the effect of blocking TCR-dependent nuclear export of HDAC7 during thymic selection, through expression of a signal-resistant mutant of HDAC7 (HDAC7-?P) in thymocytes. We find that HDAC7-?P transgenic thymocytes exhibit a profound block in negative thymic selection, but can still undergo positive selection, resulting in the escape of autoreactive T cells into the periphery. Gene expression profiling reveals a comprehensive suppression of the negative selection-associated gene expression programme in DP thymocytes, associated with a defect in the activation of MAP kinase pathways by TCR signals. The consequence of this block in vivo is a lethal autoimmune syndrome involving the exocrine pancreas and other abdominal organs. These experiments establish a novel molecular model of autoimmunity and cast new light on the relationship between thymic selection and immune self-tolerance. PMID:23103766

Kasler, Herbert G; Lim, Hyung W; Mottet, Denis; Collins, Amy M; Lee, Intelly S; Verdin, Eric

2012-11-28

331

Structural Basis of the Antiproliferative Activity of Largazole a Depsipeptide Inhibitor of the Histone Deacetylases  

SciTech Connect

Largazole is a macrocyclic depsipeptide originally isolated from the marine cyanobacterium Symploca sp., which is indigenous to the warm, blue-green waters of Key Largo, Florida (whence largazole derives its name). Largazole contains an unusual thiazoline-thiazole ring system that rigidifies its macrocyclic skeleton, and it also contains a lipophilic thioester side chain. Hydrolysis of the thioester in vivo yields largazole thiol, which exhibits remarkable antiproliferative effects and is believed to be the most potent inhibitor of the metal-dependent histone deacetylases (HDACs). Here, the 2.14 {angstrom}-resolution crystal structure of the HDAC8-largazole thiol complex is the first of an HDAC complexed with a macrocyclic inhibitor and reveals that ideal thiolate-zinc coordination geometry is the key chemical feature responsible for its exceptional affinity and biological activity. Notably, the core structure of largazole is conserved in romidepsin, a depsipeptide natural product formulated as the drug Istodax recently approved for cancer chemotherapy. Accordingly, the structure of the HDAC8-largazole thiol complex is the first to illustrate the mode of action of a new class of therapeutically important HDAC inhibitors.

K Cole; D Dowling; M Boone; A Phillips; D Christianson

2011-12-31

332

Impact of histone deacetylase 1 and metastasis-associated gene 1 expression in esophageal carcinogenesis  

PubMed Central

Animal models are important for the development of novel therapies for esophageal cancer. Histone deacetylase 1 (HDAC1)/metastasis-associated gene (MTA1) complexes inhibit p53 acetylation and thus, inhibit p53-induced apoptosis. The aim of the present study was to evaluate HDAC1 and MTA1 expression in esophageal carcinogenesis in rats. The rats underwent a total gastrectomy followed by esophagojejunostomy to induce chronic duodenal content reflux esophagitis. The rats were sacrificed sequentially at 20, 30, 40 and 50 weeks post-surgery and the esophagi were examined. Immunohistochemical analysis was conducted to assess the expression and localization of HDAC1 and MTA1. At 20 weeks post-surgery, squamous proliferative hyperplasia and Barrett’s metaplasia (BM) were observed. While, adenocarcinoma-associated BM and squamous cell carcinoma were observed at 30–50 weeks post-surgery. The nuclear expression of HDAC1 and MTA1 was observed in all of the stages of squamous carcinogenesis and adenocarcinogenesis, although not in the normal esophageal epithelium. The expression of HDAC1 and MTA1 may be involved in duodenoesophageal reflux-induced neoplastic transformation of the esophageal mucosa into cancer cells with squamous and adeno differentiation.

MIYASHITA, TOMOHARU; TAJIMA, HIDEHIRO; MUNEMOTO, MASAYOSHI; SHAH, FURHAWN A.; HARMON, JOHN W.; WATANABE, TOSHIFUMI; SHOJI, MASATOSHI; OKAMOTO, KOICHI; NAKANUMA, SHINICHI; SAKAI, SEISHO; KINOSHITA, JUN; MAKINO, ISAMU; NAKAMURA, KEISHI; HAYASHI, HIRONORI; OYAMA, KATSUNOBU; INOKUCHI, MASAFUMI; NAKAGAWARA, HISATOSHI; TAKAMURA, HIROYUKI; NINOMIYA, ITASU; KITAGAWA, HIROHISA; FUSHIDA, SACHIO; MUKAISHO, KENICHI; FUJIMURA, TAKASHI; OHTA, TETSUO

2014-01-01

333

Histone deacetylase 6 gates the synaptic action of acute stress in prefrontal cortex  

PubMed Central

The prefrontal cortex (PFC), a region responsible for high-order cognitive functions, such as decision-making, attention and working memory, is highly influenced by stress and corticosteroid stress hormones. Recently it has been shown that acute stress affects PFC functions by potentiating glutamatergic transmission via a mechanism dependent on glucocorticoid receptor (GR) and its downstream target, serum and glucocorticoid-inducible kinase (SGK). To identify the key regulators of stress responses, we examined the role of histone deacetylase 6 (HDAC6), a unique member of the HDAC family that could regulate the GR chaperone protein heat shock protein 90 (HSP90), in the synaptic action of acute stress in PFC. We found that HDAC6 inhibition or knockdown blocked the enhancement of glutamatergic transmission and glutamate receptor trafficking by acute stress in vivo or corticosterone treatment in vitro. In addition, HDAC6 inhibition blocked the up-regulation of SGK in animals exposed to acute stress. HSP90 inhibition or knockdown produced a similar blockade of the acute stress-induced enhancement of glutamatergic signalling. These findings have identified HDAC6 as a key molecule gating the effects of acute stress on synaptic functions in the PFC.

Lee, Janine B; Wei, Jing; Liu, Wenhua; Cheng, Jia; Feng, Jian; Yan, Zhen

2012-01-01

334

Dysferlin Interacts with Histone Deacetylase 6 and Increases alpha-Tubulin Acetylation  

PubMed Central

Dysferlin is a multi-C2 domain transmembrane protein involved in a plethora of cellular functions, most notably in skeletal muscle membrane repair, but also in myogenesis, cellular adhesion and intercellular calcium signaling. We previously showed that dysferlin interacts with alpha-tubulin and microtubules in muscle cells. Microtubules are heavily reorganized during myogenesis to sustain growth and elongation of the nascent muscle fiber. Microtubule function is regulated by post-translational modifications, such as acetylation of its alpha-tubulin subunit, which is modulated by the histone deacetylase 6 (HDAC6) enzyme. In this study, we identified HDAC6 as a novel dysferlin-binding partner. Dysferlin prevents HDAC6 from deacetylating alpha-tubulin by physically binding to both the enzyme, via its C2D domain, and to the substrate, alpha-tubulin, via its C2A and C2B domains. We further show that dysferlin expression promotes alpha-tubulin acetylation, as well as increased microtubule resistance to, and recovery from, Nocodazole- and cold-induced depolymerization. By selectively inhibiting HDAC6 using Tubastatin A, we demonstrate that myotube formation was impaired when alpha-tubulin was hyperacetylated early in the myogenic process; however, myotube elongation occurred when alpha-tubulin was hyperacetylated in myotubes. This study suggests a novel role for dysferlin in myogenesis and identifies HDAC6 as a novel dysferlin-interacting protein.

Di Fulvio, Sabrina; Azakir, Bilal A.; Therrien, Christian; Sinnreich, Michael

2011-01-01

335

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

PubMed

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

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

2013-12-01

336

Tetraspanin CD9 modulates human lymphoma cellular proliferation via histone deacetylase activity.  

PubMed

Non-Hodgkin Lymphoma (NHL) is a type of hematological malignancy that affects two percent of the overall population in the United States. Tetraspanin CD9 is a cell surface protein that has been thoroughly demonstrated to be a molecular facilitator of cellular phenotype. CD9 expression varies in two human lymphoma cell lines, Raji and BJAB. In this report, we investigated the functional relationship between CD9 and cell proliferation regulated by histone deacetylase (HDAC) activity in these two cell lines. Introduction of CD9 expression in Raji cells resulted in significantly increased cell proliferation and HDAC activity compared to Mock transfected Raji cells. The increase in CD9-Raji cell proliferation was significantly inhibited by HDAC inhibitor (HDACi) treatment. Pretreatment of BJAB cells with HDAC inhibitors resulted in a significant decrease in endogenous CD9 mRNA and cell surface expression. BJAB cells also displayed decreased cell proliferation after HDACi treatment. These results suggest a significant relationship between CD9 expression and cell proliferation in human lymphoma cells that may be modulated by HDAC activity. PMID:24747564

Herr, Michael J; Longhurst, Celia M; Baker, Benjamin; Homayouni, Ramin; Speich, Henry E; Kotha, Jayaprakash; Jennings, Lisa K

2014-05-16

337

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

PubMed

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

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

2012-02-15

338

Rb Interacts with Histone Deacetylase to Repress Transcription  

Microsoft Academic Search

Previously, we found that Rb can actively repress transcription of cell cycle genes by binding and inactivating transcription factors at the promoter. Here, we demonstrate that Rb can also repress transcription of endogenous cell cycle genes containing E2F sites through recruitment of histone deacetylase, which deacetylates histones on the promoter, thereby promoting formation of nucleosomes that inhibit transcription. These two

Robin X Luo; Antonio A Postigo; Douglas C Dean

1998-01-01

339

Green tea polyphenols increase p53 transcriptional activity and acetylation by suppressing class I histone deacetylases.  

PubMed

Acetylation of the tumor suppressor gene p53 at the carboxy-terminal lysine (Lys) residues enhances its transcriptional activity associated with cell cycle arrest and apoptosis. Histone deacetylases (HDACs), a family of evolutionarily conserved enzymes, counterbalance the acetylation of lysine residues on histone and non-histone proteins. In this study, we demonstrate that green tea polyphenols (GTPs) and their major constituent, (-) epigallocatechin-3-gallate (EGCG), activate p53 through acetylation at the Lys373 and Lys382 residues by inhibiting class I HDACs in LNCaP human prostate cancer cells. Treatment of cells with GTPs (2.5-10 µg/ml) and EGCG (5-20 µM) resulted in dose- and time-dependent inhibition of class I HDACs (HDAC1, 2, 3 and 8), albeit at varying levels. Discontinuation of treatment with GTP/EGCG resulted in the loss of p53 acetylation at both the sites in these cells. GTP/EGCG treatment also resulted in increased expression of p21/waf1 and Bax at the protein and message levels in these cells. The increased GTP/EGCG-mediated p53 acetylation enhanced its binding on the promoters of p21/waf1 and Bax, which was associated with increased accumulation of cells in the G0/G1 phase of the cell cycle and induction of apoptosis. Our findings indicate that GTP/EGCG causes acetylation of p53 by inhibiting class I HDACs, a function that is likely to be part of the mechanisms that control the physiological activity of p53. PMID:22552582

Thakur, Vijay S; Gupta, Karishma; Gupta, Sanjay

2012-07-01

340

Kaempferol, a new nutrition-derived pan-inhibitor of human histone deacetylases.  

PubMed

Kaempferol is a natural polyphenol belonging to the group of flavonoids. Different biological functions like inhibition of oxidative stress in plants or animal cells and apoptosis induction have been directly associated with kaempferol. The underlying mechanisms are only partially understood. Here we report for the first time that kaempferol has a distinct epigenetic activity by inhibition of histone deacetylases (HDACs). In silico docking analysis revealed that it fits into the binding pocket of HDAC2, 4, 7 or 8 and thereby binds to the zinc ion of the catalytic center. Further in vitro profiling of all conserved human HDACs of class I, II and IV showed that kaempferol inhibited all tested HDACs. In clinical oncology, HDAC inhibitors are currently under investigation as new anticancer compounds. Therefore, we studied the effect of kaempferol on human-derived hepatoma cell lines HepG2 and Hep3B as well as on HCT-116 colon cancer cells and found that it induces hyperacetylation of histone complex H3. Furthermore, kaempferol mediated a prominent reduction of cell viability and proliferation rate. Interestingly, toxicity assays revealed signs of relevant cellular toxicity in primary human hepatocytes only starting at 50 ?M as well as in an in vivo chicken embryotoxicity assay at 200 ?M. In conclusion, the identification of a novel broad inhibitory capacity of the natural compound kaempferol for human-derived HDAC enzymes opens up the perspective for clinical application in both tumor prevention and therapy. Moreover, kaempferol may serve as a novel lead structure for chemical optimization of pharmacokinetics, pharmacology or inhibitory activities. PMID:23159065

Berger, Alexander; Venturelli, Sascha; Kallnischkies, Mascha; Böcker, Alexander; Busch, Christian; Weiland, Timo; Noor, Seema; Leischner, Christian; Weiss, Thomas S; Lauer, Ulrich M; Bischoff, Stephan C; Bitzer, Michael

2013-06-01

341

Histone deacetylase inhibitor-mediated radiosensitization of human cancer cells: class differences and the potential influence of p53.  

PubMed

Histone deacetylase inhibitors (HDI) are emerging as potentially useful components of the anticancer armamentarium and as useful tools to dissect mechanistic pathways. HDIs that globally inhibit histone deacetylases (HDAC) have radiosensitizing effects, but the relative contribution of specific HDAC classes remains unclear. Newly characterized HDIs are now available that preferentially inhibit specific HDAC classes, including SK7041 (inhibits class I HDACs) and splitomicin (inhibits class III HDACs). We investigated in human cancer cells the relative radiosensitizations that result from blocking specific HDAC classes. We found that trichostatin A (TSA; inhibitor of both class I and II HDACs) was the most effective radiosensitizer, followed by the class I inhibitor SK7041, whereas splitomicin (inhibitor of class III) had least effect. Interestingly, radiosensitization by TSA in cell lines expressing p53 was more pronounced than in isogenic lines lacking p53. Radiosensitization of cells expressing p53 by TSA was reduced by pifithrin-alpha, a small-molecule inhibitor of p53. In contrast, the radiosensitization by TSA of cells expressing low levels of p53 was enhanced by transfection of wild-type p53-expressing vector or pretreatment with leptomycin B, an inhibitor of nuclear export that increased intracellular levels of p53. These effects on radiosensitization were respectively muted or not seen in cells treated with SK7041 or splitomicin. To our knowledge, this may be among the first systematic investigations of the comparative anticancer effects of inhibiting specific classes of HDACs, with results suggesting differences in the degrees of radiosensitization, which in some cell lines may be influenced by p53 expression. PMID:16467109

Kim, In Ah; Shin, Jin Hee; Kim, Il Han; Kim, Jin Ho; Kim, Jae Sung; Wu, Hong Gyun; Chie, Eui Kyu; Ha, Sung Whan; Park, Charn Il; Kao, Gary D

2006-02-01

342

Methods of Treating Cancer with HDAC Inhibitors.  

National Technical Information Service (NTIS)

The present invention provides methods of treating cancers, chemoprevention, selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells, and/or inhibiting histone deacetylase (HDAC) by administration of pharmace...

C. M. Paradise J. H. Chiao N. G. Bacopoulos T. A. Miller V. M. Richon

2006-01-01

343

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.

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

344

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.

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

2013-01-01

345

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.

2013-01-01

346

Histone Deacetylase Inhibitors: Advancing Therapeutic Strategies in Hematological and Solid Malignancies  

PubMed Central

Advancement in the understanding of cancer development in recent years has identified epigenetic abnormalities as a common factor in both tumorigenesis and refractory disease. One such event is the dysregulation of histone deacetylases (HDACs) in both hematological and solid tumors, and has consequently resulted in the development of HDAC inhibitors (HDACI) to overcome this. HDACI exhibit pleiotropic biological effects including inhibition of angiogenesis and the induction of autophagy and apoptosis. Although HDACI exhibit modest results as single agents in preclinical and clinical data, they often fall short, and therefore HDACI are most promising in combinational strategies with either standard treatments or with other experimental chemotherapies and targeted therapies. This review will discuss the induction of autophagy and apoptosis and the inhibition of angiogenesis by HDACI, and also pre-clinical and clinical combination strategies using these agents.

Ellis, Leigh; Pili, Roberto

2010-01-01

347

Cyclic Phosphatidic Acid Inhibits Alkyl-Glycerophosphate-Induced Downregulation of Histone Deacetylase 2 Expression and Suppresses the Inflammatory Response in Human Coronary Artery Endothelial Cells  

PubMed Central

Activation of the endothelium by alkyl-glycerophosphate (AGP) has been implicated in the development of atherosclerosis. Our previous study suggested that cyclic phosphatidic acid (cPA) inhibits arterial wall remodeling in a rat model in vivo. However, the mechanisms through which specific target genes are regulated during this process remain unclear. Here, we examined whether cPA inhibited AGP-induced expression of class I histone deacetylases (HDACs, namely HDAC1, HDAC2, HDAC3, and HDAC8), which may affect subsequent transcriptional activity of target genes. Our experimental results showed that human coronary artery endothelial cells (HCAECs) expressed high levels of HDAC2 and low levels HDAC1, HDAC3, and HDAC8. Moreover, AGP treatment induced downregulation of HDAC2 expression in HCAECs. However, cotreatment with cPA inhibited this downregulation of HDAC2 expression. Interestingly, treatment with AGP increased the expression and secretion of endogenous interleukin (IL)-6 and IL-8; however, this effect was inhibited when HCAECs were cotreated with cPA or the synthetic peroxisome proliferator-activator receptor gamma (PPAR?) antagonist T0070907. Thus, our data suggested that cPA may have beneficial effects in inflammation-related cardiovascular disease by controlling HDAC2 regulation.

Tsukahara, Tamotsu; Haniu, Hisao; Matsuda, Yoshikazu

2014-01-01

348

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

349

Impairment of liver regeneration by the histone deacetylase inhibitor valproic acid in mice*  

PubMed Central

Background and objective: Liver regeneration is a complex process regulated by a group of genetic and epigenetic factors. A variety of genetic factors have been reported, whereas few investigations have focused on epigenetic regulation during liver regeneration. In the present study, valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, was used to investigate the effect of HDAC on liver regeneration. Methods: VPA was administered via intraperitoneal injection to 2/3 partially hepatectomized mice to detect hepatocyte proliferation during liver regeneration. The mice were sacrificed, and their liver tissues were harvested at sequential time points from 0 to 168 h after treatment. DNA synthesis was detected via a BrdU assay, and cell proliferation was tested using Ki-67. The expressions of cyclin D1, cyclin E, cyclin dependent kinase 2 (CDK2), and CDK4 were detected by Western blot analysis. Chromatin immunoprecipitation (ChIP) assay was used to examine the recruitment of HDACs to the target promoter regions and the expression of the target gene was detected by Western blot. Results: Immunohistochemical analysis showed that cells positive for BrdU and Ki-67 decreased, and the peak of BrdU was delayed in the VPA-administered mice. Consistently, cyclin D1 expression was also delayed. We identified B-myc as a target gene of HDACs by complementary DNA (cDNA) microarray. The expression of B-myc increased in the VPA-administered mice after hepatectomy (PH). The ChIP assay confirmed the presence of HDACs at the B-myc promoter. Conclusions: HDAC activities are essential for liver regeneration. Inhibiting HDAC activities delays liver regeneration and induces liver cell cycle arrest, thereby causing an anti-proliferative effect on liver regeneration.

Ke, Qi; Yang, Rui-na; Ye, Feng; Wang, Yu-jia; Wu, Qiong; Li, Li; Bu, Hong

2012-01-01

350

A Nitric Oxide-dependent Cross-talk between Class I and III Histone Deacetylases Accelerates Skin Repair*  

PubMed Central

In a mouse model of skin repair we found that the class I-IIa histone deacetylase inhibitor trichostatin A accelerated tissue regeneration. Unexpectedly, this effect was suppressed by Sirtinol, a class III histone deacetylase (HDAC) (sirtuin)-selective inhibitor. The role of sirtuins (SIRTs) was then investigated by using resveratrol and a novel SIRT1-2-3 activator, the MC2562 compound we synthesized recently. Both resveratrol and MC2562 were effective in accelerating wound repair. The local administration of natural or synthetic SIRT activators, in fact, significantly accelerated skin regeneration by increasing keratinocyte proliferation. In vitro experiments revealed that the activation of SIRTs stimulated keratinocyte proliferation via endothelial NO synthase phosphorylation and NO production. In this condition, the class I member HDAC2 was found S-nitrosylated on cysteine, a post-transduction modification associated with loss of activity and DNA binding capacity. After deacetylase inhibitor or SIRT activator treatment, ChIP showed, in fact, a significant HDAC2 detachment from the promoter region of insulin growth factor I (IGF-I), fibroblast growth factor 10 (FGF-10), and Epithelial Growth Factor (EGF), which may be the final recipients and effectors of the SIRT-NO-HDAC signaling cascade. Consistently, the effect of SIRT activators was reduced in the presence of NG-nitro-l-arginine methyl ester (l-NAME), a general inhibitor of NO synthesis. In conclusion, the NO-dependent cross-talk among class III and I histone deacetylases suggests an unprecedented signaling pathway important for skin repair.

Spallotta, Francesco; Cencioni, Chiara; Straino, Stefania; Nanni, Simona; Rosati, Jessica; Artuso, Simona; Manni, Isabella; Colussi, Claudia; Piaggio, Giulia; Martelli, Fabio; Valente, Sergio; Mai, Antonello; Capogrossi, Maurizio C.; Farsetti, Antonella; Gaetano, Carlo

2013-01-01

351

A nitric oxide-dependent cross-talk between class I and III histone deacetylases accelerates skin repair.  

PubMed

In a mouse model of skin repair we found that the class I-IIa histone deacetylase inhibitor trichostatin A accelerated tissue regeneration. Unexpectedly, this effect was suppressed by Sirtinol, a class III histone deacetylase (HDAC) (sirtuin)-selective inhibitor. The role of sirtuins (SIRTs) was then investigated by using resveratrol and a novel SIRT1-2-3 activator, the MC2562 compound we synthesized recently. Both resveratrol and MC2562 were effective in accelerating wound repair. The local administration of natural or synthetic SIRT activators, in fact, significantly accelerated skin regeneration by increasing keratinocyte proliferation. In vitro experiments revealed that the activation of SIRTs stimulated keratinocyte proliferation via endothelial NO synthase phosphorylation and NO production. In this condition, the class I member HDAC2 was found S-nitrosylated on cysteine, a post-transduction modification associated with loss of activity and DNA binding capacity. After deacetylase inhibitor or SIRT activator treatment, ChIP showed, in fact, a significant HDAC2 detachment from the promoter region of insulin growth factor I (IGF-I), fibroblast growth factor 10 (FGF-10), and Epithelial Growth Factor (EGF), which may be the final recipients and effectors of the SIRT-NO-HDAC signaling cascade. Consistently, the effect of SIRT activators was reduced in the presence of NG-nitro-L-arginine methyl ester (L-NAME), a general inhibitor of NO synthesis. In conclusion, the NO-dependent cross-talk among class III and I histone deacetylases suggests an unprecedented signaling pathway important for skin repair. PMID:23463510

Spallotta, Francesco; Cencioni, Chiara; Straino, Stefania; Nanni, Simona; Rosati, Jessica; Artuso, Simona; Manni, Isabella; Colussi, Claudia; Piaggio, Giulia; Martelli, Fabio; Valente, Sergio; Mai, Antonello; Capogrossi, Maurizio C; Farsetti, Antonella; Gaetano, Carlo

2013-04-19

352

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.

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

353

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

354

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.

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

355

Thiamine biosynthesis in Saccharomyces cerevisiae is regulated by the NAD+-dependent histone deacetylase Hst1.  

PubMed

Genes encoding thiamine biosynthesis enzymes in microorganisms are tightly regulated such that low environmental thiamine concentrations activate transcription and high concentrations are repressive. We have determined that multiple thiamine (THI) genes in Saccharomyces cerevisiae are also regulated by the intracellular NAD(+) concentration via the NAD(+)-dependent histone deacetylase (HDAC) Hst1 and, to a lesser extent, Sir2. Both of these HDACs associate with a distal region of the affected THI gene promoters that does not overlap with a previously defined enhancer region bound by the thiamine-responsive Thi2/Thi3/Pdc2 transcriptional activators. The specificity of histone H3 and/or H4 deacetylation carried out by Hst1 and Sir2 at the distal promoter region depends on the THI gene being tested. Hst1/Sir2-mediated repression of the THI genes occurs at the level of basal expression, thus representing the first set of transcription factors shown to actively repress this gene class. Importantly, lowering the NAD(+) concentration and inhibiting the Hst1/Sum1 HDAC complex elevated the intracellular thiamine concentration due to increased thiamine biosynthesis and transport, implicating NAD(+) in the control of thiamine homeostasis. PMID:20439498

Li, Mingguang; Petteys, Brian J; McClure, Julie M; Valsakumar, Veena; Bekiranov, Stefan; Frank, Elizabeth L; Smith, Jeffrey S

2010-07-01

356

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

357

Histone deacetylase 3 unconventional splicing mediates endothelial-to-mesenchymal transition through transforming growth factor ?2.  

PubMed

Histone deacetylase 3 (HDAC3) plays a critical role in the maintenance of endothelial integrity and other physiological processes. In this study, we demonstrated that HDAC3 undergoes unconventional splicing during stem cell differentiation. Four different splicing variants have been identified, designated as HD3?, -?, -?, and -?, respectively. HD3? was confirmed in stem cell differentiation by specific antibody against the sequences from intron 12. Immunofluorescence staining indicated that the HD3? isoform co-localized with CD31-positive or ?-smooth muscle actin-positive cells at different developmental stages of mouse embryos. Overexpression of HD3? reprogrammed human aortic endothelial cells into mesenchymal cells featuring an endothelial-to-mesenchymal transition (EndMT) phenotype. HD3? directly interacts with HDAC3 and Akt1 and selectively activates transforming growth factor ?2 (TGF?2) secretion and cleavage. TGF?2 functioned as an autocrine and/or paracrine EndMT factor. The HD3?-induced EndMT was both PI3K/Akt- and TGF?2-dependent. This study provides the first evidence of the role of HDAC3 splicing in the maintenance of endothelial integrity. PMID:24045946

Zeng, Lingfang; Wang, Gang; Ummarino, Dario; Margariti, Andriana; Xu, Qihe; Xiao, Qingzhong; Wang, Wen; Zhang, Zhongyi; Yin, Xiaoke; Mayr, Manuel; Cockerill, Gillian; Li, Julie Yi-shuan; Chien, Shu; Hu, Yanhua; Xu, Qingbo

2013-11-01

358

The inhibitors of histone deacetylase suberoylanilide hydroxamate and trichostatin A release nitric oxide upon oxidation  

PubMed Central

Suberoylanilide hydroxamic acid (SAHA, vorinostat, Zolinza®) is the lead compound of a new class of histone deacetylase (HDAC) inhibitors used as anticancer drugs, which have been shown to affect multiple proteins associated with gene expression, cell proliferation and migration. Studies have also demonstrated the essential role of the hydroxamate moiety of SAHA in HDAC inhibition. The ability of SAHA and its structural analog Trichostatin A (TSA) in generating NO upon oxidation was tested directly by spin trapping of NO using Electron Paramagnetic Resonance (EPR) spectroscopy and also indirectly via the determination of nitrite using the Griess assay. H2O2/metmyoglobin was used to oxidize SAHA and TSA. These studies demonstrate for the first time, the release of NO from SAHA and its structural analog TSA. We tested the protective effects of SAHA, TSA and valproic acid (VPA) in mammalian Chinese hamster V79 cells exposed to a bolus H2O2 for 1 hour and monitoring the clonogenic cell survival. Both SAHA and TSA afforded significant cytoprotection when co-incubated with H2O2 whereas VPA was ineffective. These studies provide evidence for the release of NO by hydroxamate containing HDAC inhibitors and their antioxidant effects. Such roles may be an added advantage of this class of HDAC agents which are used for epigenetic therapies in cancer.

Samuni, Yuval; Flores-Santana, Wilmarie; Krishna, Murali C.; Mitchell, James B.; Wink, David A.

2009-01-01

359

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

360

The histone deacetylase inhibitor valproic acid sensitizes human and canine osteosarcoma to doxorubicin  

PubMed Central

Purpose Osteosarcoma (OS) remains an incurable and ultimately fatal disease in many patients, and novel forms of therapy are needed. Improved models of OS that more closely mimic human disease would provide more robust information regarding the utility of novel therapies. Spontaneous OS in dogs may provide such a model. Pharmacologic inhibition of histone deacetylase (HDAC) enzymes has a variety of anti-tumor effects but may demonstrate the most utility when utilized in combination with standard cytotoxic therapies. We sought to determine the in vitro and in vivo effects of the HDAC inhibitor valproic acid (VPA) on doxorubicin (DOX) sensitivity in canine and human OS. Methods We evaluated the in vitro anti-proliferative and apoptotic effects of VPA/DOX combination treatment, alterations in histone acetylation and nuclear DOX accumulation resulting from VPA treatment, and the in vivo efficacy of combination therapy in a xenograft model. Results Treatment of canine and human OS cell lines with clinically achievable VPA concentrations resulted in increased histone acetylation but modest anti-proliferative effects. Pre-incubation with VPA followed by doxorubicin (DOX) resulted in significant growth inhibition and potentiation of apoptosis, associated with a dose-dependent increase in nuclear DOX accumulation. The combination of VPA and DOX was superior to either monotherapy in a canine OS xenograft model. Conclusion These results demonstrate a rationale for the addition of HDAC inhibitors to current protocols for the treatment of OS and illustrate the similarities in response to HDAC inhibitors between human and canine OS, lending further credibility to the canine OS model.

Bisson, Liam; Rose, Barbara J.; Korch, Christopher; Thamm, Douglas H.

2010-01-01

361

Dephosphorylation at a Conserved SP Motif Governs cAMP Sensitivity and Nuclear Localization of Class IIa Histone Deacetylases*  

PubMed Central

Histone deacetylase 4 (HDAC4) and its paralogs, HDAC5, -7, and -9 (all members of class IIa), possess multiple phosphorylation sites crucial for 14-3-3 binding and subsequent nuclear export. cAMP signaling stimulates nuclear import of HDAC4 and HDAC5, but the underlying mechanisms remain to be elucidated. Here we show that cAMP potentiates nuclear localization of HDAC9. Mutation of an SP motif conserved in HDAC4, -5, and -9 prevents cAMP-stimulated nuclear localization. Unexpectedly, this treatment inhibits phosphorylation at the SP motif, indicating an inverse relationship between the phosphorylation event and nuclear import. Consistent with this, leptomycin B-induced nuclear import and adrenocorticotropic hormone (ACTH) treatment result in the dephosphorylation at the motif. Moreover, the modification synergizes with phosphorylation at a nearby site, and similar kinetics was observed for both phosphorylation events during myoblast and adipocyte differentiation. These results thus unravel a previously unrecognized mechanism whereby cAMP promotes dephosphorylation and differentially regulates multisite phosphorylation and the nuclear localization of class IIa HDACs.

Walkinshaw, Donald R.; Weist, Ryan; Xiao, Lin; Yan, Kezhi; Kim, Go-Woon; Yang, Xiang-Jiao

2013-01-01

362

Histone Deacetylase 7 Functions as a Key Regulator of Genes Involved in both Positive and Negative Selection of Thymocytes?  

PubMed Central

Histone deacetylase 7 (HDAC7) is highly expressed in CD4+/CD8+ thymocytes and functions as a signal-dependent repressor of gene transcription during T-cell development. In this study, we expressed HDAC7 mutant proteins in a T-cell line and use DNA microarrays to identify transcriptional targets of HDAC7 in T cells. The changes in gene expression levels were compared to differential gene expression profiles associated with positive and negative thymic selection. This analysis reveals that HDAC7 regulates an extensive set of genes that are differentially expressed during both positive and negative thymic selection. Many of these genes play important functional roles in thymic selection, primarily via modulating the coupling between antigen receptor engagement and downstream signaling events. Consistent with the model that HDAC7 may play an important role in both positive and negative thymic selection, the expression of distinct HDAC7 mutants or the abrogation of HDAC7 expression can either enhance or inhibit the signal-dependent differentiation of a CD4+/CD8+ cell line.

Kasler, Herbert G.; Verdin, Eric

2007-01-01

363

Histone Deacetylase Inhibitor Impairs Plasminogen Activator Inhibitor-1 Expression via Inhibiting TNF-?-Activated MAPK/AP-1 Signaling Cascade  

PubMed Central

Tumor necrosis factor-(TNF-)-? upregulates plasminogen activator inhibitor-(PAI-) 1 expression in pleural mesothelial cells (PMCs), contributing to fibrin deposition and pleural fibrosis. Histone deacetylases (HDACs) have been found implicated in fibrogenesis. However, the roles of TNF-? or HDAC in the regulation of PAI-1 expression have not been well investigated. We aimed to examine the effects and mechanisms of HDAC inhibition on TNF-?-induced PAI-1 expression in human PMCs. MeT-5A human PMCs were treated with TNF-? in the presence or absence of the m-carboxycinnamic acid bishydroxamide (CBHA), an HDAC class II inhibitor, and the HDAC activity, PAI-1 protein expression, mRNA, and activated signalings were analyzed. CBHA abrogated TNF-?-induced HDAC activity, PAI-1 protein and, mRNA expression in MeT-5A cells. Moreover, CBHA significantly enhanced mitogen-activated protein kinase phosphatase-(MKP-) 5/MKP-1 expression and inhibited p38/JNK activations, ATF2/c-Jun translocation, and PAI-1 promoter activity. Altogether, our data suggest that HDAC inhibition may abrogate TNF-?-activated MAPK/AP-1 signaling and PAI-1 expression in human PMCs. Given the antifibrotic effect through PAI-1 abrogation, CBHA may be utilized as a novel agent in the treatment of fibrotic diseases.

Chen, Wei-Lin; Sheu, Joen-Rong; Hsiao, Che-Jen; Hsiao, Shih-Hsin; Chung, Chi-Li

2014-01-01

364

Histone deacetylase inhibitor impairs plasminogen activator inhibitor-1 expression via inhibiting TNF-?-activated MAPK/AP-1 signaling cascade.  

PubMed

Tumor necrosis factor-(TNF-)-? upregulates plasminogen activator inhibitor-(PAI-) 1 expression in pleural mesothelial cells (PMCs), contributing to fibrin deposition and pleural fibrosis. Histone deacetylases (HDACs) have been found implicated in fibrogenesis. However, the roles of TNF-? or HDAC in the regulation of PAI-1 expression have not been well investigated. We aimed to examine the effects and mechanisms of HDAC inhibition on TNF-?-induced PAI-1 expression in human PMCs. MeT-5A human PMCs were treated with TNF-? in the presence or absence of the m-carboxycinnamic acid bishydroxamide (CBHA), an HDAC class II inhibitor, and the HDAC activity, PAI-1 protein expression, mRNA, and activated signalings were analyzed. CBHA abrogated TNF-?-induced HDAC activity, PAI-1 protein and, mRNA expression in MeT-5A cells. Moreover, CBHA significantly enhanced mitogen-activated protein kinase phosphatase-(MKP-) 5/MKP-1 expression and inhibited p38/JNK activations, ATF2/c-Jun translocation, and PAI-1 promoter activity. Altogether, our data suggest that HDAC inhibition may abrogate TNF-?-activated MAPK/AP-1 signaling and PAI-1 expression in human PMCs. Given the antifibrotic effect through PAI-1 abrogation, CBHA may be utilized as a novel agent in the treatment of fibrotic diseases. PMID:24707477

Chen, Wei-Lin; Sheu, Joen-Rong; Hsiao, Che-Jen; Hsiao, Shih-Hsin; Chung, Chi-Li; Hsiao, George

2014-01-01

365

Histone deacetylase inhibition with trichostatin A does not reverse severe angioproliferative pulmonary hypertension in rats (2013 Grover Conference series)  

PubMed Central

Abstract Pulmonary arterial hypertension (PAH) is a rapidly progressive and devastating disease characterized by remodeling of lung vessels, increased pulmonary vascular resistance, and eventually right ventricular hypertrophy and failure. Because histone deacetylase (HDAC) inhibitors are agents hampering tumor growth and cardiac hypertrophy, they have been attributed a therapeutic potential for patients with PAH. Outcomes of studies evaluating the use of HDAC inhibitors in models of PAH and right ventricular pressure overload have been equivocal, however. Here we describe the levels of HDAC activity in the lungs and hearts of rats with pulmonary hypertension and right heart hypertrophy or failure, experimentally induced by monocrotaline (MCT), the combined exposure to the VEGF-R inhibitor SU5416 and hypoxia (SuHx), and pulmonary artery banding (PAB). We show that HDAC activity levels are reduced in the lungs of rat with experimentally induced hypertension, whereas activity levels are increased in the hypertrophic hearts. In contrast to what was previously found in the MCT model, the HDAC inhibitor trichostatin A had no effect on pulmonary vascular remodeling in the SuHx model. When our results and those in the published literature are taken together, it is suggested that the effects of HDAC inhibitors in humans with PAH and associated RV failure are, at best, unpredictable. Significant progress can perhaps be made by using more specific HDAC inhibitors, but before clinical tests in human PAH can be undertaken, careful preclinical studies are required to determine potential cardiotoxicity.

2014-01-01

366

Histone deacetylase 1 phosphorylation at S421 and S423 is constitutive in vivo, but dispensable in vitro.  

PubMed

Histone Deacetylase 1 (HDAC1) is a transcriptional regulator associated with proliferation, apoptosis, and tumorigenesis, although its precise cellular role is unclear. HDAC1 was previously characterized as a phosphoprotein where mutation of phosphorylated S421 and S423 resulted in a loss of deacetylase activity and protein association. Here, the role of phosphorylation in regulating HDAC1 function was examined using phospho-specific antibodies. The antibody studies revealed that phosphorylation at S421 and S423 is constant during the cell cycle, under stress conditions, or in the presence of kinase or phosphatase inhibitors. Further, phosphorylation is dispensable for catalysis or protein association in vitro, as revealed by phosphatase studies. Truncation mutants of HDAC1 demonstrated that binding to Sin3A is promoted by S421 and S423 phosphorylation, while interaction with RbAp48 is not. Taken together, the data are consistent with constitutive phosphorylation of HDAC1 at S421 and S423 in vivo, which is dispensable for activity in vitro. PMID:17643391

Karwowska-Desaulniers, Paulina; Ketko, Anastasia; Kamath, Nayana; Pflum, Mary Kay H

2007-09-21

367

Histone deacetylase 1 phosphorylation at S421 and S423 is constitutive in vivo, but dispensable in vitro  

SciTech Connect

Histone Deacetylase 1 (HDAC1) is a transcriptional regulator associated with proliferation, apoptosis, and tumorigenesis, although its precise cellular role is unclear. HDAC1 was previously characterized as a phosphoprotein where mutation of phosphorylated S421 and S423 resulted in a loss of deacetylase activity and protein association. Here, the role of phosphorylation in regulating HDAC1 function was examined using phospho-specific antibodies. The antibody studies revealed that phosphorylation at S421 and S423 is constant during the cell cycle, under stress conditions, or in the presence of kinase or phosphatase inhibitors. Further, phosphorylation is dispensable for catalysis or protein association in vitro, as revealed by phosphatase studies. Truncation mutants of HDAC1 demonstrated that binding to Sin3A is promoted by S421 and S423 phosphorylation, while interaction with RbAp48 is not. Taken together, the data are consistent with constitutive phosphorylation of HDAC1 at S421 and S423 in vivo, which is dispensable for activity in vitro.

Karwowska-Desaulniers, Paulina [Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, MI 48202 (United States); Ketko, Anastasia [Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, MI 48202 (United States); Kamath, Nayana [Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, MI 48202 (United States); Pflum, Mary Kay H. [Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, MI 48202 (United States)]. E-mail: pflum@chem.wayne.edu

2007-09-21

368

A novel histone deacetylase inhibitor, CG200745, potentiates anticancer effect of docetaxel in prostate cancer via decreasing Mcl-1 and Bcl XL  

Microsoft Academic Search

Summary  We synthesized a novel hydroxamate-based pan-histone deacetylase inhibitor (HDACI), CG200745 {(E)-2-(Naphthalen-1-yloxymethyl)-oct-2-enedioic\\u000a acid 1-[(3-dimethylamino-propyl)-amide] 8-hydroxyamide]}. Like other inhibitors, for example vorinostat and belinostat, CG200745\\u000a has the hydroxamic acid moiety to bind zinc at the bottom of catalytic pocket. Firstly, we analyzed its inhibitory activity\\u000a against histone deacetylase (HDAC) in hormone-dependent LNCaP cells and hormone-independent DU145 and PC3 cells. CG200745\\u000a inhibited deacetylation

Jung Jin Hwang; Yong Sook Kim; Taelim Kim; Mi Joung Kim; In Gab Jeong; Je-Hwan Lee; Jene Choi; Sejin Jang; Seonggu Ro; Choung-Soo Kim

369

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.

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

2014-01-01