Review on HDAC3 (histone deacetylase 3), with data on DNA, on the protein encoded, and where the gene is implicated

Escaffit, F

Atlas of Genetics and Cytogenetics in Oncology and Haematology

I-Revues

 
 
 
 
 
 
Gene Section 
Review 
 
Atlas Genet Cytogenet Oncol Haematol. 2008;12(2)  104 
Atlas of Genetics and Cytogenetics 
in Oncology and Haematology                         
                         OPEN ACCESS JOURNAL AT INIST-CNRS 
HDAC3 (histone deacetylase 3) 
Fabrice Escaffit 
Chromatin and Cell Proliferation group, LBCMCP-UMR 5088 CNRS, Université Paul Sabatier, Bât 4R3B1, 
118, route de Narbonne, 31062 Toulouse Cedex 9, France 
Published in Atlas Database: August 2007 
Online updated version: http://AtlasGeneticsOncology.org/Genes/HDAC3ID40804ch5q31.html  
DOI: 10.4267/2042/38492 
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. 
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology 
 
Identity 
Hugo: HDAC3 
Other names: HDAC3; HD3; RPD3-2; RPD3; 
SMAP45 
Location: 5q31.3 
Local order: 140,980,626 pb to 140,996,596 bp in 
minus strand orientation 
DNA/RNA 
Description 
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). 
Transcription 
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. 
Pseudogene 
No pseudogene have been described. 
 
Protein 
Note: 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. 
Description 
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. 
 
 
 
HDAC3 (histone deacetylase 3) Escaffit F 
 
 
 
 
 
Atlas Genet Cytogenet Oncol Haematol. 2008;12(2)  105 
 
 
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. 
Expression 
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). 
Localisation 
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. 
Function 
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 no
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 te 
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 (histone deacetylase 3) Escaffit F 
 
 
 
 
 
Atlas Genet Cytogenet Oncol Haematol. 2008;12(2)  106 
Homology 
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. 
Mutations 
Note: 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 
Cancers 
Note: 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). 
Disease 
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. 
Prognosis 
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. 
Oncogenesis 
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. 
Neurodegenerative and neuromuscular 
diseases 
Note: 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. 
References 
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corepressors are activating cofactors for histone deacetylase 
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associates with and represses the transcription factor GATA-2. 
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Schroeder TM, Kahler RA, Li X, Westendorf JJ. Histone 
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HDAC3 (histone deacetylase 3) Escaffit F 
 
 
 
 
 
Atlas Genet Cytogenet Oncol Haematol. 2008;12(2)  107 
Gregoire S, Xiao L, Nie J, Zhang X, Xu M, Li J, Wong J, Seto 
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This article should be referenced as such: 
Escaffit F. HDAC3 (histone deacetylase 3). Atlas Genet 
Cytogenet Oncol Haematol. 2008;12(2):104-107.  
 
 
 


HDAC3 (histone deacetylase 3)

http://documents.irevues.inist.fr/bitstream/2042/38492/2/08-2007-HDAC3ID40804ch5q31.pdf

HDAC3 (histone deacetylase 3)

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