Histone deacetylase 2
Histone deacetylase 2 (HDAC2) is an enzyme that in humans is encoded by the HDAC2 gene.[5] It belongs to the histone deacetylase class of enzymes responsible for the removal of acetyl groups from lysine residues at the N-terminal region of the core histones (H2A, H2B, H3, and H4). As such, it plays an important role in gene expression by facilitating the formation of transcription repressor complexes and for this reason is often considered an important target for cancer therapy.[6]
Though the functional role of the class to which HDAC2 belongs has been carefully studied, the mechanism by which HDAC2 interacts with histone deacetylases of other classes has yet to be elucidated. HDAC2 is broadly regulated by protein kinase 2 (CK2) and protein phosphatase 1 (PP1), but biochemical analysis suggests its regulation is more complex (evinced by the coexistence of HDAC1 and HDAC2 in three distinct protein complexes).[7] Essentially, the mechanism by which HDAC2 is regulated is still unclear by virtue of its various interactions, though a mechanism involving p300/CBP-associated factor and HDAC5 has been proposed in the context of cardiac reprogramming.[8]
Generally, HDAC2 is considered a putative target for the treatment for a variety of diseases, due to its involvement in cell cycle progression. Specifically, HDAC2 has been shown to play a role in
Structure and mechanism
HDAC2 belongs to the first class of histone deactylases. The active site of HDAC2 contains a Zn2+ ion coordinated to the carbonyl group of a lysine substrate and a water molecule. The metallic ion facilitates the nucleophilic attack of the carbonyl group by a coordinated water molecule, leading to the formation of a tetrahedral intermediate. This intermediate is momentarily stabilized by hydrogen bond interactions and metal coordination, until it ultimately collapses resulting in the deacetylation of the lysine residue.[14]
The HDAC2 active site consists of a lipophilic tube which leads from the surface to the catalytic center, and a 'foot pocket' containing mostly water molecules. The active site is connected to Gly154, Phe155, His183, Phe210, and Leu276. The footpocket is connected to Tyr29, Met35, Phe114, and Leu144.[15]
Function
This gene product belongs to the histone deacetylase family. Histone deacetylases act via the formation of large multiprotein complexes and are responsible for the deacetylation of lysine residues on the N-terminal region of the core histones (H2A, H2B, H3 and H4). This protein also forms transcriptional repressor complexes by associating with many different proteins, including YY1, a mammalian zinc-finger transcription factor. Thus, it plays an important role in transcriptional regulation, cell cycle progression and developmental events.[16]
Disease relevance
Cardiac hypertrophy
HDAC2 has been shown to play a role in the regulatory pathway of cardiac hypertrophy. Deficiencies in HDAC2 were shown to mitigate cardiac hypertrophy in hearts exposed to hypertrophic stimuli. However, in HDAC2 transgenic mice with inactivated glycogen synthase kinase 3beta (Gsk3beta), hypertrophy was observed at a higher frequency. In mice with activated Gsk3beta enzymes and HDAC2 deficiencies, sensitivity to hypertrophic stimulus was observed at a higher rate. The results suggest regulatory roles of HDAC2 and GSk3beta.
Alzheimer's disease
It has been found that patients with Alzheimer's disease experience a decrease in the expression of neuronal genes.[18] Furthermore, a recent study found that inhibition of HDAC2 via c-Abl by tyrosine phosphorylation prevented cognitive and behavioral impairments in mice with Alzheimer's disease.[19] The results of the study support the role of c-Abl and HDAC2 in the signaling pathway of gene expression in patients with Alzheimer's disease. Currently, efforts to synthesize an HDAC2 inhibitor for the treatment of Alzheimer's disease are based on a pharmacophore with four features: one hydrogen bond acceptor, one hydrogen bond donor, and two aromatic rings.[9]
Parkinson's disease
HDAC inhibitors have been regarded as a potential treatment of neurodegenerative diseases, such as
Cancer therapy
The role of HDAC2 in various forms of cancer such as osteosarcoma, gastric cancer, and acute myeloid leukemia have been studied. A recent study discovered decreased metastasis formation in mouse models that develop pancreatic cancer when the murine ortholog Hdac2 was genetically depleted.[20] Current research is focused on creating inhibitors that decrease the upregulation of HDAC2.
Anti-influenza virus factor
HDAC2 plays a role in regulating the Signal Transducer and Activator of Transcription I (STAT1) and interferon-stimulated gene such as viperin. This shows that HDAC2 might be a component of cellular innate antiviral response. To circumvent the anti-viral potential, influenza A virus dysregulates HDAC2 by inducing its degradation by proteasomal degradation.[21]
Interactions
Histone deacetylase 2 has been shown to
- Ataxia telangiectasia and Rad3 related,[22]
- BUB3,[23]
- CDC20,[23]
- CDH1,[23]
- CHD3,[24][25][26]
- CHD4,[22][24][25]
- DNMT1,[27]
- EED,[28]
- EZH2[28] and
- FKBP3,[29]
- GATA4,[30]
- GTF2I,[24][31]
- HDAC10,[32]
- HDAC1,[24][25][28][32][33][34][35][36][37][38][39][40][41]
- HMG20B,[24][34]
- HSPA4,[35]
- Host cell factor C1,[42]
- MTA1,[24][33][43]
- MTA2,[24][33][39]
- MXD1,[44][45]
- Mad1,[23]
- Methyl-CpG-binding domain protein 2,[39][46][47]
- PHF21A,[24][34][48]
- PPP1R8,[49]
- RBBP4,[24][25][50][51]
- RCOR1,[34][52]
- RELA,[53][54]
- Retinoblastoma protein,[55]
- SAP30,[39][56][57]
- SIN3A,[24][25][44][50][51][58][59]
- SMARCA5,[26]
- SNW1,[60]
- SUV39H1,[61]
- Sp3 transcription factor,[62][63]
- TOP2B,[64] and
- YY1.[65][66][67]
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000196591 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000019777 - Ensembl, May 2017
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- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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Further reading
- Ahringer J (August 2000). "NuRD and SIN3 histone deacetylase complexes in development". Trends in Genetics. 16 (8): 351–356. PMID 10904264.
- Verdin E, Dequiedt F, Kasler HG (May 2003). "Class II histone deacetylases: versatile regulators". Trends in Genetics. 19 (5): 286–293. PMID 12711221.
- Zhang Y, Dufau ML (June 2003). "Dual mechanisms of regulation of transcription of luteinizing hormone receptor gene by nuclear orphan receptors and histone deacetylase complexes". The Journal of Steroid Biochemistry and Molecular Biology. 85 (2–5): 401–414. S2CID 28512341.
- Furukawa Y, Kawakami T, Sudo K, Inazawa J, Matsumine A, Akiyama T, Nakamura Y (1996). "Isolation and mapping of a human gene (RPD3L1) that is homologous to RPD3, a transcription factor in Saccharomyces cerevisiae". Cytogenetics and Cell Genetics. 73 (1–2): 130–133. PMID 8646880.
- Yang WM, Inouye C, Zeng Y, Bearss D, Seto E (November 1996). "Transcriptional repression by YY1 is mediated by interaction with a mammalian homolog of the yeast global regulator RPD3". Proceedings of the National Academy of Sciences of the United States of America. 93 (23): 12845–12850. PMID 8917507.
- Laherty CD, Yang WM, Sun JM, Davie JR, Seto E, Eisenman RN (May 1997). "Histone deacetylases associated with the mSin3 corepressor mediate mad transcriptional repression". Cell. 89 (3): 349–356. S2CID 13490886.
- Zhang Y, Iratni R, Erdjument-Bromage H, Tempst P, Reinberg D (May 1997). "Histone deacetylases and SAP18, a novel polypeptide, are components of a human Sin3 complex". Cell. 89 (3): 357–364. PMID 9150135.
- Yang WM, Yao YL, Sun JM, Davie JR, Seto E (October 1997). "Isolation and characterization of cDNAs corresponding to an additional member of the human histone deacetylase gene family". The Journal of Biological Chemistry. 272 (44): 28001–28007. PMID 9346952.
- Hassig CA, Tong JK, Fleischer TC, Owa T, Grable PG, Ayer DE, Schreiber SL (March 1998). "A role for histone deacetylase activity in HDAC1-mediated transcriptional repression". Proceedings of the National Academy of Sciences of the United States of America. 95 (7): 3519–3524. PMID 9520398.
- Randhawa GS, Bell DW, Testa JR, Feinberg AP (July 1998). "Identification and mapping of human histone acetylation modifier gene homologues". Genomics. 51 (2): 262–269. PMID 9722949.
- Zhang Y, LeRoy G, Seelig HP, Lane WS, Reinberg D (October 1998). "The dermatomyositis-specific autoantigen Mi2 is a component of a complex containing histone deacetylase and nucleosome remodeling activities". Cell. 95 (2): 279–289. S2CID 18786866.
- Tong JK, Hassig CA, Schnitzler GR, Kingston RE, Schreiber SL (October 1998). "Chromatin deacetylation by an ATP-dependent nucleosome remodelling complex". Nature. 395 (6705): 917–921. S2CID 4355885.
- Hsieh JJ, Zhou S, Chen L, Young DB, Hayward SD (January 1999). "CIR, a corepressor linking the DNA binding factor CBF1 to the histone deacetylase complex". Proceedings of the National Academy of Sciences of the United States of America. 96 (1): 23–28. PMID 9874765.
- Yarden RI, Brody LC (April 1999). "BRCA1 interacts with components of the histone deacetylase complex". Proceedings of the National Academy of Sciences of the United States of America. 96 (9): 4983–4988. PMID 10220405.
- Koipally J, Renold A, Kim J, Georgopoulos K (June 1999). "Repression by Ikaros and Aiolos is mediated through histone deacetylase complexes". The EMBO Journal. 18 (11): 3090–3100. PMID 10357820.
- Zhang Y, Ng HH, Erdjument-Bromage H, Tempst P, Bird A, Reinberg D (August 1999). "Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation". Genes & Development. 13 (15): 1924–1935. PMID 10444591.
- Ng HH, Zhang Y, Hendrich B, Johnson CA, Turner BM, Erdjument-Bromage H, et al. (September 1999). "MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex". Nature Genetics. 23 (1): 58–61. S2CID 6147725.
- Wade PA, Gegonne A, Jones PL, Ballestar E, Aubry F, Wolffe AP (September 1999). "Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation". Nature Genetics. 23 (1): 62–66. S2CID 52868103.
- Lai A, Lee JM, Yang WM, DeCaprio JA, Kaelin WG, Seto E, Branton PE (October 1999). "RBP1 recruits both histone deacetylase-dependent and -independent repression activities to retinoblastoma family proteins". Molecular and Cellular Biology. 19 (10): 6632–6641. PMID 10490602.
External links
- HDAC2+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- FactorBook HDAC2
- Overview of all the structural information available in the PDB for UniProt: Q92769 (Histone deacetylase 2) at the PDBe-KB.