Disease relevance of HDAC2

• We show that the upregulation of HDAC2 in colorectal cancer occurred early at the polyp stage, was more robust and occurred more frequently than HDAC1 [1].
• Although most HDAC2 is not phosphorylated in the breast cancer cells, HDAC2 bound to Sp1 and Sp3 and cross-linked to chromatin in situ is highly enriched in a phosphorylated form that has a reduced mobility in SDS-polyacrylamide gels [2].
• Closely related HDAC1 and HDAC2 do not elicit humoral response in colon cancer patients [3].
• In chronic obstructive pulmonary disease, there is a reduction in HDAC2 activity and expression, which may account for the amplified inflammation and resistance to the actions of corticosteroids [4].
• The reduction in HDAC2 may be secondary to oxidative and nitrative stress as a result of cigarette smoking and severe inflammation, and may also occur in severe asthma, smoking asthmatic patients and cystic fibrosis [4].

High impact information on HDAC2

• The presence of the HDAC2 frameshift mutation causes a loss of HDAC2 protein expression and enzymatic activity and renders these cells more resistant to the usual antiproliferative and proapoptotic effects of histone deacetylase inhibitors [5].
• We have identified truncating mutations in one of the primary human histone deacetylases, HDAC2, in sporadic carcinomas with microsatellite instability and in tumors arising in individuals with hereditary nonpolyposis colorectal cancer syndrome [5].
• DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci [6].
• Loss of Brg1 or HDAC2 should therefore produce Gc resistance, and we show that approximately 50% of Gc-resistant human and dog corticotroph adenomas, which are the hallmark of Cushing disease, are deficient in nuclear expression of either protein [7].
• In conclusion, we show that overexpression of HDAC2 in glucocorticoid-insensitive alveolar macrophages from patients with COPD is able to restore glucocorticoid sensitivity [8].

Chemical compound and disease context of HDAC2

• Interference with HDAC2 by valproic acid largely diminishes adenoma formation in APC(min) mice [9].
• There appears to be a marked reduction in histone deacetylase-2 in macrophages and peripheral lung of patients with chronic obstructive pulmonary disease, which accounts for amplified inflammation and steroid resistance [10].

Biological context of HDAC2

• Upon HDAC2 knockdown, cells displayed an increased number of cellular extensions reminiscent of cell differentiation [1].
• Finally, and perhaps most interesting, HDAC2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression [11].
• Histone deacetylase 2 (HDAC2) is a member of a large family of enzymes that alter gene expression by catalyzing the removal of acetyl groups from core histones [11].
• Together, our data indicate that like many HDACs, HDAC2 is regulated by post-translational modification, particularly phosphorylation [11].
• Originally isolated as a transcriptional co-repressor, HDAC2 possesses extensive amino acid sequence homology to HDAC1 (the founding member and most extensively studied HDAC enzyme) [11].

Anatomical context of HDAC2

• HDAC1 and HDAC2 are associated in HeLa cells in a complex that is predominantly separate from an HDAC3 immune complex [12].
• Specific knockdown of HDAC2 by RNA interference resulted in reduced sensitivity to dexamethasone suppression of interleukin 1beta-induced granulocyte/macrophage colony-stimulating factor production [8].
• A complex of EBNA3C and ProTalpha coimmunoprecipitated with HDAC1 and HDAC2 in cell lines stably expressing EBNA3C [13].
• In this report, we show that EBNA3C complexed with ProTalpha can also recruit deacetylase activity and associates in a complex that includes HDAC1 and HDAC2 in human B cells [13].
• Likewise, treatment of HT-29 cells with the HDAC inhibitor valproic acid leads to a moderate inhibition of cell cycle progression in the G1 phase whereas interference with HDAC2 expression does not [14].

Associations of HDAC2 with chemical compounds

• Significantly, upon addition of T3, the NRE further recruited the thyroid hormone receptor (TRbeta) and another deacetylase, HDAC2 [15].
• TSA treatment increased the acetylation of the transcription factors Sp1 and C/EBPalpha and decreased their binding as well as the binding of CBP and HDAC2 to the bcl-2 promoters [16].
• The N-terminal leucine-abundant region of PELP1 was observed to interact with HDAC2 and exhibited repressive activity when tethered to the chromatin [17].
• Furthermore, coimmunoprecipitation experiments indicated that HDAC10v1 associated with HDAC2 and SMRT (silencing mediator for retinoid and thyroid hormone receptors) [18].
• Hyperphosphorylated HDAC2 was also observed in cells synchronized with nocodazole or taxol, demonstrating regulation of HDAC phosphorylation during mitosis [19].

Regulatory relationships of HDAC2

• Testicular zinc finger protein recruits histone deacetylase 2 and suppresses the transactivation function and intranuclear foci formation of agonist-bound androgen receptor competitively with TIF2 [20].
• In contrast to other HDAC inhibitors VPA also induces proteasomal degradation of HDAC2 [21].
• Corticosteroids, the most effective anti-inflammatory drugs so far available, recruit HDAC2 to activated inflammatory gene complexes through an interaction with glucocorticoid receptor and thus switch off activated inflammatory genes [22].
• HDAC2 inhibition in ESS-1 cells caused significant changes in the cell cycle by inhibiting G(1)-S transition and influencing expression of p21(WAF1) and cyclin D1 [23].
• Mxi1 and HDAC2 were up-regulated by N-Myc in an myc-inducible cell line and in N-myc-expressing cell lines [24].

Other interactions of HDAC2

• The class I deacetylases HDAC1 and HDAC2 are components of multisubunit complexes, one of which could associate with the nuclear hormone receptor corepressor, N-CoR [25].
• CHD4 (also called Mi-2beta) is a component of a histone-deacetylase-2 (HDAC2)-containing complex, the nucleosome remodeling and deacetylating (NRD) complex [26].
• Molecular association between ATR and two components of the nucleosome remodeling and deacetylating complex, HDAC2 and CHD4 [26].
• Sequence comparison suggested that the HD2-type histone deacetylases and the FKBP-type PPIases may have evolved from a common ancestor enzyme [27].
• In addition, like HDAC1, the phospho-acceptor sites in HDAC2 are located in the C-terminal portion of the protein [11].

Analytical, diagnostic and therapeutic context of HDAC2

• Furthermore, using chromatin immunoprecipitation assay, we demonstrated that HDAC2 was present in the INK4d proximal promoter region in the absence, but not the presence, of TSA [28].
• There was no difference in the site of HDAC1-HDAC6 expression between normal subjects and subjects with asthma, but subjects with asthma had reduced HDAC enzymatic activity and reduced HDAC1 and HDAC2 protein expression, as measured by Western blotting [29].
• Here, in order to investigate the possible role of HDAC2 in gastric carcinogenesis, we analyzed the expression of HDAC2 in 71 gastric adenocarcinomas by immunohistochemistry [30].
• Our results suggest that HDAC2 might be considered as potential drug target in the therapy of ESS and that HDAC inhibitors should be further evaluated in clinical trials in ESS [23].
• The interaction mapped to the C-terminus of IRS-1 and was confirmed through co-immunoprecipitation in vitro of recombinant IRS-1 and HDAC2 [31].

References