| Written | 2010-01 | Santiago Ropero, Manel Esteller |
| Departamento de Bioquimica y Biologia Molecular, Facultad de Medicina, Universidad de Alcala, 28871 Alcala de Henares, Madrid, Spain (SR); Cancer Epigenetics, Biology Program (PEBC), Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), 08907 L'Hospitalet, Barcelona, Catalonia, Spain (ME) | ||
| Updated | 2014-01 | Hyun Jin Bae, Suk Woo Nam |
| Department of Pathology, College of Medicine, Functional RNomics Research Center, The Catholic University of Korea, Banpo-dong, Seocho-gu, Seoul, Korea |
| Identity |
| Alias_symbol (synonym) | RPD3 |
| YAF1 | |
| Other alias | EC 3.5.1.98 |
| HD2 | |
| HGNC (Hugo) | HDAC2 |
| LocusID (NCBI) | 3066 |
| Atlas_Id | 40803 |
| Location | 6q21 [Link to chromosome band 6q21] |
| Location_base_pair | Starts at 113936156 and ends at 113971195 bp from pter ( according to hg19-Feb_2009) [Mapping HDAC2.png] |
| Fusion genes (updated 2016) | HDAC2 (6q21) / AK9 (6q21) | HDAC2 (6q21) / MATN2 (8q22.1) | HDAC2 (6q21) / TRDN (6q22.31) |
| UCHL5 (1q31.2) / HDAC2 (6q21) |
| DNA/RNA |
 | |
| Description | The HDAC2 gene is composed of 14 exons that span 35.029 bp of genomic DNA. |
| Transcription | The length of the transcribed mRNA is about 6659 bp. |
| Pseudogene | No pseudogene has been described. |
| Protein |
 | |
| Description | There are two proteins variants of 488 and 582 aa due to distinct pre-mRNA splicing events. The N-terminal tail of the protein contains the catalytic domain that comprises most of the protein. The N-terminal domain also has a HDAC association domain (HAD) essential for homo- and heterodimerization. A coiled-coil domain essential for protein-protein interactions is present at the C-terminal tail. It also contains three phosphorylation sites at Ser394, Ser422 and Ser424, and two S-nitrosylation sites at Cys262 and Cys274. |
| Expression | Widely expressed. |
| Localisation | Nucleus. |
| Function | HDAC2 belongs to class I histone deacetylases that also comprise HDAC1, HDAC3 and HDAC8. HDAC2 acts as a transcriptional repressor through the desacetylation of lysine residues present at the N-terminal tail of histone proteins (H2A, H2B, H3 and H4). HDAC2 heterodimerise with HDAC1, but the heterodimer cannot bind to DNA, so they have to be recruited by transcription factors such as YY1, SP1/SP3, the tumor suppressor genes p53 and BRCA1. HDAC2 can also be tethered to DNA as a part of the multiprotein corepressor complexes CoREST, mSin3 and NuRD. These complexes are targeted to specific genomic sequences by interactions with sequence-specific transcription factors. For example, the HDAC2/HDAC1 containing Sin3-SAP corepressor complex is recruited by E2F family of transcription factors to repress transcription. HDAC2 containing complexes are also implicated in gene transcription-regulation mediated by nuclear receptors. These complexes also contain other epigenetic modifier genes, such as methyl-binding proteins (MeCp2), the DNA methyl transferases DNMT1, DNMT3A and DNMT3B, the histone methyl transferases SUVAR39H1 and G9a and histone demethylases (LSD1), providing another way by which HDAC2 regulates gene expression and chromatin remodelling. HDAC2 also regulates gene expression through the deacetylation of specific transcription factors that includes STAT3 and SMAD7. HDAC2 is a key regulator of genes regulating cell cycle, apoptosis, cell adhesion and migration. Together with HDAC1, HDAC2 regulates the transcription of genes implicated in haematopoiesis, epithelial cell differentiation, heart development and neurogenesis. Montgomery et al. (2007) find that HDAC2 and HDAC1 double-null mice show an uncontrolled ventricular proliferation, while Trivedi and collegues (2007) show the lack of cardiac hypertrophy in HDAC2 mutant mice. HDAC2 is also a key regulator of nervous system function acting as a repressor of synaptic plasticity genes that regulates learning and memory formation. HDAC2-deficient mouse have enhanced memory formation. |
| Homology | The histone deacetylase domain of HDAC2 is highly homologous to other class I HDACs (HDAC1, HDAC3 and HDAC8) showing the greater homology with HDAC1. This domain is also highly conserved between species (from yeast to human). |
| Mutations |
| Germinal | No germinal mutations have been found. |
| Somatic | HDAC2 is mutated in sporadic tumors with microsatellite instability and in tumors arising in individuals with hereditary non-polyposis colorectal carcinoma. This mutation consists in a deletion of a nine adenines repeat present in Exon1 that produce a truncated and inactive form of the protein. The expression of the mutant form of HDAC2 induces resistance to the proapoptotic and antiproliferative effects of HDAC inhibitors. The lack of HDAC2 expression and function produces the up-regulation of tumor-growth promoting genes. |
| Implicated in |
| Note | |
| Entity | Various cancers |
| Note | The deregulation of HDAC2 expression and activity has been linked to cancer development. HDAC2 is overexpressed in different tumor types including colon, gastric, cervical, prostate carcinoma, non-small cell lung cancer, and hepatocellular carcinoma. HDAC2 overexpression is implicated in cancer partly through its aberrant recruitment and consequent silencing of tumor suppressor genes. The repression of the tumor suppressor gene p21WAF1 is associated with histone hypoacetylation at the promoter region and can be reversed by the treatment with HDAC inhibitors. |
| Prognosis | HDAC2 expression is correlated with poor prognosis and advanced stage disease in colorectal, prostate, gastric and hepatocellular carcinomas. |
| Entity | Colon cancer |
| Note | There are a number of studies showing HDAC2 overexpression in colon cancer. The increase of HDAC2 expression has been found at the protein and mRNA level indicating that HDAC2 overexpression is due to transcriptional activation. These studies indicate that in this tumor type HDAC2 transcription is regulated by beta-catenin-TCF-myc signaling pathway that is deregulated in colon cancer. HDAC2 overexpression is correlated with poor prognosis and advanced stage disease in colorectal carcinoma. However, Ropero et al., found an inactivating mutation of HDAC2 in colon cancers with microsatellite instability. |
| Entity | Breast cancer |
| Note | Different studies show an important role of HDAC2 in breast cancer. HDAC2 Knockdown induces senescence in breast cancer cells. Moreover the loss of HDAC2 activity potentiates the apoptotic effect of tamoxifen in estrogen/progesterone positive breast cancer cells. |
| Entity | Prostate cancer |
| Note | Weichert et al., found that HDAC2 was strongly expressed in more than 70% of prostate cancer cases analyzed. The increase in HDAC2 expression was associated with enhanced tumor cell proliferation and poor prognosis in prostate cancer suggesting HDAC2 as a novel prognostic factor in this tumor type. |
| Entity | Hepatocellular carcinoma |
| Note | HDAC2 regulated cell cycle and disruption of HDAC2 caused G1/S arrest in cell cycle. In G1/S transition, targeted-disruption of HDAC2 selectively induced the expression of p16(INK4A) and p21(WAF1/Cip1), and simultaneously suppressed the expression of cyclin D1, CDK4 and CDK2. Consequently, HDAC2 inhibition led to the down-regulation of E2F/DP1 target genes through a reduction in phosphorylation status of pRb protein. |
| Entity | Gastric cancer |
| Note | HDAC2 is aberrantly up-regulated in gastric cancers. HDAC2 inactivation significantly reduced cell motility, cell invasion, clonal expansion, and tumor growth. HDAC2 knockdown-induced G(1)-S cell cycle arrest and restored activity of p16(INK4a) and the proapoptotic factors. |
| Entity | Lung cancer |
| Note | HDAC2 is highly up-regulated in lung cancer. HDAC2 inactivation resulted in regression of tumor cell growth and activation of cellular apoptosis via p53 and Bax activation and Bcl2 suppression. In cell cycle regulation, HDAC2 inactivation caused induction of p21WAF1/CIP1 expression, and simultaneously suppressed the expressions of cyclin E2, cyclin D1, and CDK2, respectively. Consequently, this led to the hypophosphorylation of pRb protein in G1/S transition and thereby inactivated E2F/DP1 target gene transcriptions of A549 cells. HDAC2 directly regulated p21WAF1/CIP1 expression in a p53-independent manner. |
| Entity | Chronic obstructive pulmonary disease (COPD) |
| Note | Reduced HDAC2 activity and expression is found in chronic obstructive pulmonary disease (COPD). The reduced activity of HDAC2 produces the upregulation of genes implicated in the inflammatory response and resistance to corticosteroids in COPD. |
| Bibliography |
| Role of HDAC2 in the pathophysiology of COPD. |
| Barnes PJ. |
| Annu Rev Physiol. 2009;71:451-64. (REVIEW) |
| PMID 18817512 |
| Selective inhibition of histone deacetylase 2 silences progesterone receptor-mediated signaling. |
| Bicaku E, Marchion DC, Schmitt ML, Munster PN. |
| Cancer Res. 2008 Mar 1;68(5):1513-9. |
| PMID 18316616 |
| Histone deacetylase HDAC1/HDAC2-controlled embryonic development and cell differentiation. |
| Brunmeir R, Lagger S, Seiser C. |
| Int J Dev Biol. 2009;53(2-3):275-89. (REVIEW) |
| PMID 19412887 |
| Histone deacetylase 1 can repress transcription by binding to Sp1. |
| Doetzlhofer A, Rotheneder H, Lagger G, Koranda M, Kurtev V, Brosch G, Wintersberger E, Seiser C. |
| Mol Cell Biol. 1999 Aug;19(8):5504-11. |
| PMID 10409740 |
| Dnmt3a binds deacetylases and is recruited by a sequence-specific repressor to silence transcription. |
| Fuks F, Burgers WA, Godin N, Kasai M, Kouzarides T. |
| EMBO J. 2001 May 15;20(10):2536-44. |
| PMID 11350943 |
| HDAC2 negatively regulates memory formation and synaptic plasticity. |
| Guan JS, Haggarty SJ, Giacometti E, Dannenberg JH, Joseph N, Gao J, Nieland TJ, Zhou Y, Wang X, Mazitschek R, Bradner JE, DePinho RA, Jaenisch R, Tsai LH. |
| Nature. 2009 May 7;459(7243):55-60. |
| PMID 19424149 |
| Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1/WAF1 expression, independent of histone deacetylase 1. |
| Huang BH, Laban M, Leung CH, Lee L, Lee CK, Salto-Tellez M, Raju GC, Hooi SC. |
| Cell Death Differ. 2005 Apr;12(4):395-404. |
| PMID 15665816 |
| Histone deacetylases specifically down-regulate p53-dependent gene activation. |
| Juan LJ, Shia WJ, Chen MH, Yang WM, Seto E, Lin YS, Wu CW. |
| J Biol Chem. 2000 Jul 7;275(27):20436-43. |
| PMID 10777477 |
| HDAC2 overexpression confers oncogenic potential to human lung cancer cells by deregulating expression of apoptosis and cell cycle proteins. |
| Jung KH, Noh JH, Kim JK, Eun JW, Bae HJ, Xie HJ, Chang YG, Kim MG, Park H, Lee JY, Nam SW. |
| J Cell Biochem. 2012 Jun;113(6):2167-77. doi: 10.1002/jcb.24090. |
| PMID 22492270 |
| Targeted inactivation of HDAC2 restores p16INK4a activity and exerts antitumor effects on human gastric cancer. |
| Kim JK, Noh JH, Eun JW, Jung KH, Bae HJ, Shen Q, Kim MG, Chang YG, Kim SJ, Park WS, Lee JY, Borlak J, Nam SW. |
| Mol Cancer Res. 2013 Jan;11(1):62-73. doi: 10.1158/1541-7786.MCR-12-0332. Epub 2012 Nov 21. |
| PMID 23175521 |
| Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility. |
| Montgomery RL, Davis CA, Potthoff MJ, Haberland M, Fielitz J, Qi X, Hill JA, Richardson JA, Olson EN. |
| Genes Dev. 2007 Jul 15;21(14):1790-802. |
| PMID 17639084 |
| Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. |
| Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN, Bird A. |
| Nature. 1998 May 28;393(6683):386-9. |
| PMID 9620804 |
| Aberrant regulation of HDAC2 mediates proliferation of hepatocellular carcinoma cells by deregulating expression of G1/S cell cycle proteins. |
| Noh JH, Jung KH, Kim JK, Eun JW, Bae HJ, Xie HJ, Chang YG, Kim MG, Park WS, Lee JY, Nam SW. |
| PLoS One. 2011;6(11):e28103. doi: 10.1371/journal.pone.0028103. Epub 2011 Nov 23. |
| PMID 22132221 |
| S-Nitrosylation of histone deacetylase 2 induces chromatin remodelling in neurons. |
| Nott A, Watson PM, Robinson JD, Crepaldi L, Riccio A. |
| Nature. 2008 Sep 18;455(7211):411-5. Epub 2008 Aug 27. |
| PMID 18754010 |
| E2F mediates cell cycle-dependent transcriptional repression in vivo by recruitment of an HDAC1/mSin3B corepressor complex. |
| Rayman JB, Takahashi Y, Indjeian VB, Dannenberg JH, Catchpole S, Watson RJ, te Riele H, Dynlacht BD. |
| Genes Dev. 2002 Apr 15;16(8):933-47. |
| PMID 11959842 |
| Transforming pathways unleashed by a HDAC2 mutation in human cancer. |
| Ropero S, Ballestar E, Alaminos M, Arango D, Schwartz S Jr, Esteller M. |
| Oncogene. 2008 Jun 26;27(28):4008-12. Epub 2008 Feb 11. |
| PMID 18264134 |
| The role of histone deacetylases (HDACs) in human cancer. |
| Ropero S, Esteller M. |
| Mol Oncol. 2007 Jun;1(1):19-25. Epub 2007 Mar 7. (REVIEW) |
| PMID 19383284 |
| A truncating mutation of HDAC2 in human cancers confers resistance to histone deacetylase inhibition. |
| Ropero S, Fraga MF, Ballestar E, Hamelin R, Yamamoto H, Boix-Chornet M, Caballero R, Alaminos M, Setien F, Paz MF, Herranz M, Palacios J, Arango D, Orntoft TF, Aaltonen LA, Schwartz S Jr, Esteller M. |
| Nat Genet. 2006 May;38(5):566-9. Epub 2006 Apr 16. |
| PMID 16642021 |
| Epigenetic regulation of hematopoietic differentiation by Gfi-1 and Gfi-1b is mediated by the cofactors CoREST and LSD1. |
| Saleque S, Kim J, Rooke HM, Orkin SH. |
| Mol Cell. 2007 Aug 17;27(4):562-72. |
| PMID 17707228 |
| Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3 beta activity. |
| Trivedi CM, Luo Y, Yin Z, Zhang M, Zhu W, Wang T, Floss T, Goettlicher M, Noppinger PR, Wurst W, Ferrari VA, Abrams CS, Gruber PJ, Epstein JA. |
| Nat Med. 2007 Mar;13(3):324-31. Epub 2007 Feb 18. |
| PMID 17322895 |
| Functional and physical interaction between the histone methyl transferase Suv39H1 and histone deacetylases. |
| Vaute O, Nicolas E, Vandel L, Trouche D. |
| Nucleic Acids Res. 2002 Jan 15;30(2):475-81. |
| PMID 11788710 |
| Histone deacetylases 1, 2 and 3 are highly expressed in prostate cancer and HDAC2 expression is associated with shorter PSA relapse time after radical prostatectomy. |
| Weichert W, Roske A, Gekeler V, Beckers T, Stephan C, Jung K, Fritzsche FR, Niesporek S, Denkert C, Dietel M, Kristiansen G. |
| Br J Cancer. 2008 Feb 12;98(3):604-10. Epub 2008 Jan 22. |
| PMID 18212746 |
| HDAC expression and clinical prognosis in human malignancies. |
| Weichert W. |
| Cancer Lett. 2009 Aug 8;280(2):168-76. Epub 2008 Dec 21. (REVIEW) |
| PMID 19103471 |
| Histone deacetylase inhibitors: molecular mechanisms of action. |
| Xu WS, Parmigiani RB, Marks PA. |
| Oncogene. 2007 Aug 13;26(37):5541-52. (REVIEW) |
| PMID 17694093 |
| Transcriptional repression by YY1 is mediated by interaction with a mammalian homolog of the yeast global regulator RPD3. |
| Yang WM, Inouye C, Zeng Y, Bearss D, Seto E. |
| Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):12845-50. |
| PMID 8917507 |
| The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men. |
| Yang XJ, Seto E. |
| Nat Rev Mol Cell Biol. 2008 Mar;9(3):206-18. (REVIEW) |
| PMID 18292778 |
| BRCA1 interacts with components of the histone deacetylase complex. |
| Yarden RI, Brody LC. |
| Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):4983-8. |
| PMID 10220405 |
| Induction of HDAC2 expression upon loss of APC in colorectal tumorigenesis. |
| Zhu P, Martin E, Mengwasser J, Schlag P, Janssen KP, Gottlicher M. |
| Cancer Cell. 2004 May;5(5):455-63. |
| PMID 15144953 |
| Citation |
| This paper should be referenced as such : |
| Bae, HJ ; Nam, SW |
| HDAC2 (histone deacetylase 2) |
| Atlas Genet Cytogenet Oncol Haematol. 2014;18(8):594-597. |
| Free journal version : [ pdf ] [ DOI ] |
| On line version : http://AtlasGeneticsOncology.org/Genes/HDAC2ID40803ch6q22.html |
| History of this paper: |
| Ropero, S ; Esteller, M. HDAC2 (histone deacetylase 2). Atlas Genet Cytogenet Oncol Haematol. 2010;14(10):966-969. |
| http://documents.irevues.inist.fr/bitstream/handle/2042/44871/01-2010-HDAC2ID40803ch6q22.pdf |
| Other Leukemias implicated (Data extracted from papers in the Atlas) [ 7 ] |
| External links |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Wed Jun 7 12:04:21 CEST 2017 |
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