HDAC3 (histone deacetylase 3)

2007-08-01   Fabrice Escaffit 

Chromatin, Cell Proliferation group, LBCMCP-UMR 5088 CNRS, Université Paul Sabatier, Bät 4R3B1, 118, route de Narbonne, 31062 TOULOUSE Cedex 9, France




Atlas Image


The HDAC3 gene consists of 15 exons and spans 15.97 kb of genomic sequence on chromosome 5 (from position 140,980,626 pb to 140,996,596 bp, in minus strand orientation).


The mRNA transcribed from this gene is 1,934 nucleotides long. There are actually two described isoforms resulting from an alternative splicing in the 5 region.


No pseudogene have been described.



HDAC3 interacts with other proteins, such as HDAC1, HDAC7, HDAC10, DACH1, YY1, DAXX, PML, RB1, RELA, JUN, SIN3A, BCOR, JMJD2A/JHDM3A, AKAP95, KLF6, DLK1, TR2, NRIP1 and SRY. Also described as a component of the N-CoR/SMRT repressor complexes by interacting with NCOR1/NCOR2.
Atlas Image


The HDAC3 protein is 428 amino acids long (isoelectric point: 4.98) and belongs to the class I histone deacetylase subfamily.
In spite of the presence of a sequence ressembling the canonical NES at the position 29-41, CRM1 binding is observed in the region 180-313 and these residues act as a NES (or as a binding site for a NES-containing protein) that uses CRM1 export pathway. A NLS has been characterised in the C-terminal region (313-428). Another important sequence, required for oligomerisation of HDAC3 with itself and for the cell viability, is present in the N-terminal part (1-122) of the protein.
The HDAC3 protein can be phosphorylated on Ser424 by Caseine Kinase 2 and the same residue is dephosphorylated by protein serine/threonine phosphatase 4 (PP4). HDAC3 can also be symoylated in vitro.


Like the other members of class I HDACs, HDAC3 is widely expressed in organisms, whereas HDACs of other classes are tissue-specific.
Two different isoforms of HDAC3 are expressed depending on an alternative splicing of the mRNA. The resulting proteins differ in their first 15 N-terminal amino acids (MAKTVAYFYDPDVGN -> MIVFKPYQASQHDMCR).


As opposed to other class I HDACs that have been found predominantly nuclear, HDAC3 is located in both nuclear and cytoplasmic compartments as well as at the plasma membrane.


In accordance to the limited homology of HDAC3 with the other HDACs (particularly in the C-terminal part of the protein) and its specific subcellular localisation, HDAC3 plays specific roles in the cell physiology and has substrates in the various cell compartments. Thus, unlike HDAC1/HDAC2, HDAC3 is required for cell growth and is involved in the apoptotic process of almost all cell types via the regulation of pro-apoptotic genes. Moreover, HDAC3 has been suggested to have a role in the cytoplasm, notably in signal transduction since it is a substrate of the membrane associated tyrosine kinase Src. So, in organisms, this protein plays a critical role in development, inflammation and metabolism.
As the other histone deacetylases, HDAC3 acts on the chromatin via the formation of large multiprotein complexes. But unlike HDAC1/2, that are implicated in the formation of Sin3, NuRD and CoREST complexes, HDAC3 is present in specific complexes containing members of the nuclear receptor co-repressor family N-CoR/SMRT (Silencing Mediator of Retinoid acid and Thyroid hormone receptor). HDAC3 is responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4) that correlates with epigenetic repression. This deacetylation is involved in transcriptional regulation of genes important for cell cycle progression and development. Thus, HDAC3 has been implicated to play roles in governing cell proliferation via the inhibition of p15(INK4b) and p21(WAF1/cip1).
Many transcription factors can directly interact with HDAC3 and thus, may target the histone deacetylase to specific promoters. Thus, HDAC3 is able to regulate osteoblast differentiation and bone formation via its association with the osteoblast master protein, Runx2, and the inhibition of the trans-activity of Runx2. Likewise, in hematopoietic stem cells, HDAC3, but not other class I HDACs, directly associates with GATA-2 and suppresses its key transcriptional potential.
The deacetylase activity of HDAC-3 can also target non-histone proteins: for example, HDAC3 is responsible in the inhibition of the myogenesis via its association with the acetyltransferases p300 and p300/CBP-associated factor (PCAF) to reverse autoacetylation and thus, to repress the p300/PCAF/MEF2-dependent transcription.
So, HDAC3 regulates many biological processes in a complex multi-levels manner.
The activity of HDAC3 is regulated by the phosphorylation of the Ser424 residue of the protein (see protein description above) and CK2 and PP4 are responsible for this regulation. Interaction with the other members within multiprotein complexes also regulates the deacetylase activity of HDAC3 (the nuclear receptor corepressor SMRT stimulated this activity towards MEF2 and PCAF). HDAC3 activity can also be indirectly regulated by post-translational modification of its associated proteins (for example, the phosphorylation of SMRT induces the disruption of the complex and the de-repression of the target promoter). The cleavage of the HDAC3 protein is another type of regulation affecting this enzyme: thus, during apoptosis, removal of the C-terminal part of HDAC3 results in accumulation of the cleaved protein in the cytoplasm and so, in its inactivation towards nuclear histones (but a possible role of the cleaved protein in the cytoplasm cannot be excluded).


HDAC3 is very tightly conserved from plants to human. The histone deacetylase domain of HDAC3 (amino acids 3 to 316) is partly homologous to the other class I HDACs (HDAC1, HDAC2 and HDAC8) whereas C-terminal part of the protein is highly divergent. So, the HDAC3 protein is about 50% identical compared with other class I HDACs.



No mutation is actually known for HDAC3 but Single Nucleotide Polymorphisms have been described in mRNA UTR (TGGGGG/TTCACC), introns (GATCTA/GTATTA; AAGGAA/CACAAT; GAAGGA/GCCCAT; AAACTA/GTAAAA) or in exons where it induces synonymous (TCATGT/CTGGGA (Q/Q)) or non-synonymous (ACCCAA/GTGAGT (N/S); CCAATC/GGATCA (R/P)) coding (non-exhaustive list).

Implicated in

Entity name
Phase I/II clinical trials are actually conducted in north America with isoselective inhibitors of class I HDACs for the treatment of the Hodgkin lymphoma (HDACs inhibitors alone), of the acute myeloid leukemia and myelodysplastic syndrome (in association with DNA methylation inhibitors) or of pancreatic cancers (in association with antimetabolites).
Histone Deacetylase 3 and other class I HDACs, that regulate cell maturation and p21 expression, are deregulated in numerous cancers such as colon, ovary, lung, stomach, muscle, bone or skin cancers. The overexpression of HDAC3 is observed in almost tumoral pathologies. The downregulation of HDAC3 in colon cancer cells, in which the enzyme is normally overexpressed, results in cell growth inhibition, differentiation and increased apoptosis.
HDAC3 in combination with other antigens may become a useful molecular biomarker with diagnostic or prognostic value for a subset of colon cancer patients.
There is no correlation between HDAC3 polymorphism and the risk of lung cancer .
HDAC3 was shown to be recruited by the tumor antigen MAGE-A to block the activation of the tumor suppressor p53. In leukaemia, the generation of oncogenic fusion proteins (TEL-AML1, ETO-AML1, MTG16a-AML1, PLZF-RARalpha) causes aberrant recruitment of N-CoR/SMRT-HDAC3 repressor complexes on promoters. Moreover, nuclear HDAC3 plays an anti-apoptotic role that is important for cancer cell growth.
Entity name
Neurodegenerative and neuromuscular diseases
Clinical trials are conducted with class I HDACs isoselective inhibitors for the treatment of Spinal Muscular Atrophy.
HDAC inhibitors are also tested to enhance neuronal survival in both in vitro and in vivo models of neurodegenerative diseases such as polyglutamine-related diseases and amyotrophic lateral sclerosis.


Pubmed IDLast YearTitleAuthors
167719052006Epigenetics of lung cancer.Bowman RV et al
95011691998Characterization of a human RPD3 ortholog, HDAC3.Emiliani S et al
171017902007Cleavage and cytoplasmic relocalization of histone deacetylase 3 are important for apoptosis progression.Escaffit F et al
171589262007Histone deacetylase 3 interacts with and deacetylates myocyte enhancer factor 2.Grégoire S et al
115096522001The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3.Guenther MG et al
162983432006Histone deacetylase 3 represses p15(INK4b) and p21(WAF1/cip1) transcription by interacting with Sp1.Huang W et al
176940852007HDAC3: taking the SMRT-N-CoRrect road to repression.Karagianni P et al
165320302006Histone deacetylase 3 localizes to the plasma membrane and is a substrate of Src.Longworth MS et al
115679982001Histone deacetylase 3 associates with and represses the transcription factor GATA-2.Ozawa Y et al
152922602004Histone deacetylase 3 interacts with runx2 to repress the osteocalcin promoter and regulate osteoblast differentiation.Schroeder TM et al
159812152005Antibody response to a non-conserved C-terminal part of human histone deacetylase 3 in colon cancer patients.Shebzukhov YV et al
165338122006Histone deacetylase 3 (HDAC3) and other class I HDACs regulate colon cell maturation and p21 expression and are deregulated in human colon cancer.Wilson AJ et al
117798482002Functional domains of histone deacetylase-3.Yang WM et al
158054702005Histone deacetylase 3 (HDAC3) activity is regulated by interaction with protein serine/threonine phosphatase 4.Zhang X et al

Other Information

Locus ID:

NCBI: 8841
MIM: 605166
HGNC: 4854
Ensembl: ENSG00000171720


dbSNP: 8841
ClinVar: 8841
TCGA: ENSG00000171720


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Viral carcinogenesisKEGGhsa05203
Viral carcinogenesisKEGGko05203
Thyroid hormone signaling pathwayKEGGhsa04919
Metabolism of proteinsREACTOMER-HSA-392499
Protein foldingREACTOMER-HSA-391251
Chaperonin-mediated protein foldingREACTOMER-HSA-390466
Association of TriC/CCT with target proteins during biosynthesisREACTOMER-HSA-390471
Organelle biogenesis and maintenanceREACTOMER-HSA-1852241
Mitochondrial biogenesisREACTOMER-HSA-1592230
Transcriptional activation of mitochondrial biogenesisREACTOMER-HSA-2151201
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
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
Circadian ClockREACTOMER-HSA-400253
BMAL1:CLOCK,NPAS2 activates circadian gene expressionREACTOMER-HSA-1368108
RORA activates gene expressionREACTOMER-HSA-1368082
NR1D1 (REV-ERBA) represses gene expressionREACTOMER-HSA-1368071
Metabolism of lipids and lipoproteinsREACTOMER-HSA-556833
Fatty acid, triacylglycerol, and ketone body metabolismREACTOMER-HSA-535734
Regulation of lipid metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha)REACTOMER-HSA-400206
PPARA activates gene expressionREACTOMER-HSA-1989781
Developmental BiologyREACTOMER-HSA-1266738
Transcriptional regulation of white adipocyte differentiationREACTOMER-HSA-381340
Chromatin organizationREACTOMER-HSA-4839726
Chromatin modifying enzymesREACTOMER-HSA-3247509
HDACs deacetylate histonesREACTOMER-HSA-3214815
Activation of HOX genes during differentiationREACTOMER-HSA-5619507
Activation of anterior HOX genes in hindbrain development during early embryogenesisREACTOMER-HSA-5617472

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
233950022013Repression of the long noncoding RNA-LET by histone deacetylase 3 contributes to hypoxia-mediated metastasis.213
119317682002The N-CoR-HDAC3 nuclear receptor corepressor complex inhibits the JNK pathway through the integral subunit GPS2.192
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
222309542012Structure of HDAC3 bound to co-repressor and inositol tetraphosphate.149
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
118675392002Control of cytomegalovirus lytic gene expression by histone acetylation.111
230796602012Coordinated silencing of MYC-mediated miR-29 by HDAC3 and EZH2 as a therapeutic target of histone modification in aggressive B-Cell lymphomas.106
157610262005The orphan nuclear receptor Rev-erbalpha recruits the N-CoR/histone deacetylase 3 corepressor to regulate the circadian Bmal1 gene.105
152922602004Histone deacetylase 3 interacts with runx2 to repress the osteocalcin promoter and regulate osteoblast differentiation.99
155724452004Human cytomegalovirus immediate-early 1 protein facilitates viral replication by antagonizing histone deacetylation.98


Fabrice Escaffit

HDAC3 (histone deacetylase 3)

Atlas Genet Cytogenet Oncol Haematol. 2007-08-01

Online version: http://atlasgeneticsoncology.org/gene/40804/hdac3