Disease relevance of HDAC3

• Silencing of HDAC3 expression in colon cancer cell lines resulted in growth inhibition, a decrease in cell survival, and increased apoptosis [1].
• Here we demonstrate increased protein expression of HDAC3 in human colon tumors and in duodenal adenomas from Apc1638(N/+) mice [1].
• Comparison with gene microarray data revealed that 31% of the differentially regulated proteins correlate with altered mRNA expression in squamous cell lung carcinomas, including PEX1, MKK7 and HDAC3 for up-regulated proteins [2].
• Antisense RNA oligonucleotides for HDAC3 enhanced apoptosis 48 h after hyperthermia at 43 degrees C for 30 min in vivo [3].
• To further explore the catalytic activity of HDACs, we expressed two additional human class I HDACs, HDAC1 and HDAC3, in baculovirus [4].

High impact information on HDAC3

• Here we report that HDAC3 is a critical, transcription-independent regulator of mitosis [5].
• HDAC3 forms a complex with A-Kinase-Anchoring Proteins AKAP95 and HA95, which are targeted to mitotic chromosomes [5].
• Early studies have suggested that HDAC3 activity is regulated by association with the corepressors N-CoR and SMRT [6].
• Interestingly, unlike other class I HDACs, HDAC3 uniquely copurifies with the catalytic and regulatory subunits of the protein serine/threonine phosphatase 4 complex (PP4c/PP4R1) [6].
• Here we demonstrate that, in addition to protein-protein interactions with NCoR/SMRT, the activity of HDAC3 is regulated by both phosphorylation and dephosphorylation [6].

Chemical compound and disease context of HDAC3

• Chemotherapy of Hodgkin's lymphoma with alternating cycles of COPP (cyclophosphamide, vincristin, procarbazine, prednisone) and ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine). Results of the HD1 and HD3 trials of the German Hodgkin Study Group [7].

Biological context of HDAC3

• Histone deacetylase 3 (HDAC3) is one of four members of the human class I HDACs that regulates gene expression by deacetylation of histones and nonhistone proteins [6].
• The strict control of HDAC3 activity underscores the cellular imperative that histone deacetylation occur only in targeted regions of the genome [8].
• Binding of HDAC3 and MBD1 is not confined to the promoter region but instead is spread over the locus [9].
• We have screened the expressed sequence tag database (National Center for Biotechnology Information) with the yeast RPD3 sequence and identified a human ortholog of RPD3, HDAC3 [10].
• Supporting the physical interaction and deacetylase activity, HDAC3 repressed MEF2-dependent transcription and inhibited myogenesis [11].

Anatomical context of HDAC3

• We show that the C-terminal region of HDAC3 protein lacking the homology to other Class I HDAC contains at least 3 distinct B-cell epitopes that are recognized by the serum antibodies [12].
• By using a specific polyclonal antiserum recognizing the C-terminal domain of HDAC3p and Western blotting, we detected a single approximately 49-kDa band in several tumor cell lines [10].
• Histone deacetylase 3 interacts with and deacetylates myocyte enhancer factor 2 [11].
• HDAC1 and HDAC2 are associated in HeLa cells in a complex that is predominantly separate from an HDAC3 immune complex [13].
• Thus, HDAC3 regulates osteoblast differentiation and bone formation [14].

Associations of HDAC3 with chemical compounds

• Histone deacetylase 3 (HDAC3) activity is regulated by interaction with protein serine/threonine phosphatase 4 [6].
• We show that the HDAC3-containing SMRT and N-CoR complexes can bind to unliganded thyroid hormone receptors (TRs) in vitro [15].
• This was associated with posttranslational modification of HDAC1, HDAC2, and HDAC3 protein by nitrotyrosine and aldehyde-adduct formation [16].
• We showed here that c-jun was transcriptionally repressed in response to osmotic stress via a truncated HDAC3 generated by caspase-7-dependent cleavage at aspartic acid 391 [17].
• In the initial phase, IKKalpha is responsible for derepressing the silencing mediator for retinoic acid and thyroid hormone receptor (SMRT)-histone deacetylase 3 (HDAC3) corepressor complex from the p50 homodimer [18].

Physical interactions of HDAC3

• Based on Western blotting using antibodies against known subunits, the only HDAC found in the N-CoR-1 complex was HDAC3 [19].
• Here we report that HDAC3 interacts with SMRT only after priming by cellular chaperones including the TCP-1 ring complex (TRiC), which is required for proper folding of HDAC3 in an ATP-dependent process [8].
• In an immunoaffinity purification using anti-HDAC3, transcription factor TFII-I copurified with HDAC3 [20].
• Assembly of the SMRT-histone deacetylase 3 repression complex requires the TCP-1 ring complex [8].
• Further investigations showed that this domain is sufficient for AR interaction and possesses the ability to bind histone deacetylase 3 [21].

Regulatory relationships of HDAC3

• Here we report that SMRT functions as an activating cofactor of HDAC3 [22].
• Histone Deacetylase 3 (HDAC3) and Other Class I HDACs Regulate Colon Cell Maturation and p21 Expression and Are Deregulated in Human Colon Cancer [1].
• LPS-mediated activation of ATF-2 was inhibited by HDAC3 in a time- and dose-dependent manner [23].
• HDAC1 protein was more abundantly expressed in SW620 cells compared with that of HDAC3 and HDAC8 [4].
• A range of concentrations of this TGF beta 1 antiserum stimulated HD3 cell growth in a dose-dependent manner, further documenting the autocrine-negative response of the cells to TGF beta 1 [24].

Other interactions of HDAC3

• PML-RARalpha recruits MBD1 to its target promoter through an HDAC3-mediated mechanism [9].
• GATA-2 directly associates with HDAC3 but not with HDAC1 [25].
• This is the first demonstration that a tissue-specific transcription factor directly and selectively interacts with HDAC3 and HDAC5 among HDAC family members [25].
• These results provide a possible molecular mechanism for HDAC3 regulation and argue that N-CoR is a platform in which distinct domains can interact with most of the known HDACs [26].
• In addition, HDAC3 associated with the acetyltransferases p300 and p300/CBP-associated factor (PCAF) to reverse autoacetylation [11].

Analytical, diagnostic and therapeutic context of HDAC3

• Immunofluorescence experiments demonstrated further that IkappaBalpha acts by partially redirecting HDAC3 to the cytoplasm [27].
• Immunoprecipitation experiments with either an antiserum against HDAC3p or an anti-FLAG antiserum and a flagged HDAC3 cDNA showed that HDAc3p exhibits deacetylase activity both on free histones and on purified nucleosomes [10].
• Specificity of the HDAC3-TFII-I interaction was confirmed by coimmunoprecipitation of epitope-tagged proteins, GST pull-down assays, and protein colocalization with indirect immunofluorescence [20].
• Using chromatin immunoprecipitation, we show recruitment of two different corepressor complexes to ER-responsive promoters in a mutually exclusive and sequential manner: the nuclear receptor corepressor-HDAC3 complex followed by nucleosome remodeling and histone deacetylation complex [28].
• Confocal microscopy and additional co-localization analysis detected nuclear HDAC3 in all tumours examined [29].

References