HDAC2 (histone deacetylase 2)

2014-01-01   Hyun Jin Bae , Suk Woo Nam 




Atlas Image


The HDAC2 gene is composed of 14 exons that span 35.029 bp of genomic DNA.


The length of the transcribed mRNA is about 6659 bp.


No pseudogene has been described.


Atlas Image


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.


Widely expressed.




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.


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).



No germinal mutations have been found.


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

Entity name
Various cancers
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.
HDAC2 expression is correlated with poor prognosis and advanced stage disease in colorectal, prostate, gastric and hepatocellular carcinomas.
Entity name
Colon cancer
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 name
Breast cancer
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 name
Prostate cancer
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 name
Hepatocellular carcinoma
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 name
Gastric cancer
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 name
Lung cancer
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 name
Chronic obstructive pulmonary disease (COPD)
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.


Pubmed IDLast YearTitleAuthors
188175122009Role of HDAC2 in the pathophysiology of COPD.Barnes PJ et al
183166162008Selective inhibition of histone deacetylase 2 silences progesterone receptor-mediated signaling.Biçaku E et al
194128872009Histone deacetylase HDAC1/HDAC2-controlled embryonic development and cell differentiation.Brunmeir R et al
104097401999Histone deacetylase 1 can repress transcription by binding to Sp1.Doetzlhofer A et al
113509432001Dnmt3a binds deacetylases and is recruited by a sequence-specific repressor to silence transcription.Fuks F et al
194241492009HDAC2 negatively regulates memory formation and synaptic plasticity.Guan JS et al
156658162005Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1/WAF1 expression, independent of histone deacetylase 1.Huang BH et al
107774772000Histone deacetylases specifically down-regulate p53-dependent gene activation.Juan LJ et al
224922702012HDAC2 overexpression confers oncogenic potential to human lung cancer cells by deregulating expression of apoptosis and cell cycle proteins.Jung KH et al
231755212013Targeted inactivation of HDAC2 restores p16INK4a activity and exerts antitumor effects on human gastric cancer.Kim JK et al
176390842007Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility.Montgomery RL et al
96208041998Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex.Nan X et al
221322212011Aberrant regulation of HDAC2 mediates proliferation of hepatocellular carcinoma cells by deregulating expression of G1/S cell cycle proteins.Noh JH et al
187540102008S-Nitrosylation of histone deacetylase 2 induces chromatin remodelling in neurons.Nott A et al
119598422002E2F mediates cell cycle-dependent transcriptional repression in vivo by recruitment of an HDAC1/mSin3B corepressor complex.Rayman JB et al
182641342008Transforming pathways unleashed by a HDAC2 mutation in human cancer.Ropero S et al
193832842007The role of histone deacetylases (HDACs) in human cancer.Ropero S et al
166420212006A truncating mutation of HDAC2 in human cancers confers resistance to histone deacetylase inhibition.Ropero S et al
177072282007Epigenetic regulation of hematopoietic differentiation by Gfi-1 and Gfi-1b is mediated by the cofactors CoREST and LSD1.Saleque S et al
173228952007Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3 beta activity.Trivedi CM et al
117887102002Functional and physical interaction between the histone methyl transferase Suv39H1 and histone deacetylases.Vaute O et al
182127462008Histone 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 et al
191034712009HDAC expression and clinical prognosis in human malignancies.Weichert W et al
176940932007Histone deacetylase inhibitors: molecular mechanisms of action.Xu WS et al
89175071996Transcriptional repression by YY1 is mediated by interaction with a mammalian homolog of the yeast global regulator RPD3.Yang WM et al
182927782008The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men.Yang XJ et al
102204051999BRCA1 interacts with components of the histone deacetylase complex.Yarden RI et al
151449532004Induction of HDAC2 expression upon loss of APC in colorectal tumorigenesis.Zhu P et al

Other Information

Locus ID:

NCBI: 3066
MIM: 605164
HGNC: 4853
Ensembl: ENSG00000196591


dbSNP: 3066
ClinVar: 3066
TCGA: ENSG00000196591


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Cell cycleKEGGko04110
Notch signaling pathwayKEGGko04330
Huntington's diseaseKEGGko05016
Chronic myeloid leukemiaKEGGko05220
Cell cycleKEGGhsa04110
Notch signaling pathwayKEGGhsa04330
Huntington's diseaseKEGGhsa05016
Pathways in cancerKEGGhsa05200
Chronic myeloid leukemiaKEGGhsa05220
Transcriptional misregulation in cancerKEGGko05202
Transcriptional misregulation in cancerKEGGhsa05202
Epstein-Barr virus infectionKEGGhsa05169
Epstein-Barr virus infectionKEGGko05169
Viral carcinogenesisKEGGhsa05203
Viral carcinogenesisKEGGko05203
Thyroid hormone signaling pathwayKEGGhsa04919
Diseases of signal transductionREACTOMER-HSA-5663202
Signaling by NOTCH1 in CancerREACTOMER-HSA-2644603
Signaling by NOTCH1 PEST Domain Mutants in CancerREACTOMER-HSA-2644602
Constitutive Signaling by NOTCH1 PEST Domain MutantsREACTOMER-HSA-2644606
Signaling by NOTCH1 HD+PEST Domain Mutants in CancerREACTOMER-HSA-2894858
Constitutive Signaling by NOTCH1 HD+PEST Domain MutantsREACTOMER-HSA-2894862
Factors involved in megakaryocyte development and platelet productionREACTOMER-HSA-983231
Signal TransductionREACTOMER-HSA-162582
Signalling by NGFREACTOMER-HSA-166520
p75 NTR receptor-mediated signallingREACTOMER-HSA-193704
p75NTR negatively regulates cell cycle via SC1REACTOMER-HSA-193670
Signaling by NOTCHREACTOMER-HSA-157118
Signaling by NOTCH1REACTOMER-HSA-1980143
NOTCH1 Intracellular Domain Regulates TranscriptionREACTOMER-HSA-2122947
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
RNA Polymerase I, RNA Polymerase III, and Mitochondrial TranscriptionREACTOMER-HSA-504046
RNA Polymerase I TranscriptionREACTOMER-HSA-73864
RNA Polymerase I Promoter ClearanceREACTOMER-HSA-73854
RNA Polymerase I Transcription InitiationREACTOMER-HSA-73762
Epigenetic regulation of gene expressionREACTOMER-HSA-212165
Negative epigenetic regulation of rRNA expressionREACTOMER-HSA-5250941
NoRC negatively regulates rRNA expressionREACTOMER-HSA-427413
Chromatin organizationREACTOMER-HSA-4839726
Chromatin modifying enzymesREACTOMER-HSA-3247509
HDACs deacetylate histonesREACTOMER-HSA-3214815
Positive epigenetic regulation of rRNA expressionREACTOMER-HSA-5250913
Longevity regulating pathway - multiple speciesKEGGko04213
Longevity regulating pathway - multiple speciesKEGGhsa04213
Regulation of TP53 ActivityREACTOMER-HSA-5633007
Regulation of TP53 Activity through AcetylationREACTOMER-HSA-6804758
ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expressionREACTOMER-HSA-427389

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
91501341997Histone deacetylases associated with the mSin3 corepressor mediate mad transcriptional repression.299
208024852010Human HDAC1 and HDAC2 function in the DNA-damage response to promote DNA nonhomologous end-joining.247
223888142012An epigenetic blockade of cognitive functions in the neurodegenerating brain.240
173228952007Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3 beta activity.185
182127462008Histone deacetylases 1, 2 and 3 are highly expressed in prostate cancer and HDAC2 expression is associated with shorter PSA relapse time after radical prostatectomy.167
209724252010GAPDH mediates nitrosylation of nuclear proteins.150
151449532004Induction of HDAC2 expression upon loss of APC in colorectal tumorigenesis.137
183471672008Class I histone deacetylase expression has independent prognostic impact in human colorectal cancer: specific role of class I histone deacetylases in vitro and in vivo.115
121402632002Daxx and histone deacetylase II associate with chromatin through an interaction with core histones and the chromatin-associated protein Dek.113
169511982006Class II histone deacetylases are associated with VHL-independent regulation of hypoxia-inducible factor 1 alpha.101


Hyun Jin Bae ; Suk Woo Nam

HDAC2 (histone deacetylase 2)

Atlas Genet Cytogenet Oncol Haematol. 2014-01-01

Online version: http://atlasgeneticsoncology.org/gene/40803/hdac2-(histone-deacetylase-2)

Historical Card

2010-01-01 HDAC2 (histone deacetylase 2) by  Santiago Ropero,Manel Esteller