Biology:Histone deacetylase 2

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Histone deacetylase 2 (HDAC2) is an enzyme that in humans is encoded by the HDAC2 gene.[1] 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.[2]

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).[3] 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.[4]

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 cardiac hypertrophy,[4] Alzheimer's disease,[5] Parkinson's disease,[6] acute myeloid leukemia (AML),[7] osteosarcoma,[8] and stomach cancer.[9]

Structure and mechanism

This image shows the structure of the HDAC2 enzyme. The two consecutive benzene rings form the foot pocket, where as the single benzene rings forms the lipophilic tube.

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.[10]

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.[11]

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.[12]

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.[13]

The HDAC2 enzyme attacking a lysine residue.

Mechanisms by which HDAC2 responds to hypertrophic stress have been proposed, though no general consensus has been met. One suggested mechanism puts forth casein kinase dependent phosphorylation of HDAC2, while a more recent mechanism suggests acetylation regulated by p300/CBP-associated factor and HDAC5.[4]

Alzheimer's disease

It has been found that patients with Alzheimer's disease experience a decrease in the expression of neuronal genes.[14] 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.[15] 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.[5]

Parkinson's disease

HDAC inhibitors have been regarded as a potential treatment of neurodegenerative diseases, such as Parkinson's disease. Parkinson's disease is usually accompanied by an increase in the number of microglial proteins in the substantia nigra of the brain. In vivo evidence has shown a correlation between the number of microglial proteins and the upregulation of HDAC2.[6] It is thought therefore that HDAC2 inhibitors could be effective in treating microglial-initiated loss of dopaminergic neurons in the brain.

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.[16] 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.[17]

Interactions

Histone deacetylase 2 has been shown to interact with:


See also

References

  1. ↑ "Human histone deacetylase 2, HDAC2 (Human RPD3), is localized to 6q21 by radiation hybrid mapping". Genomics 52 (2): 245–246. September 1998. doi:10.1006/geno.1998.5435. PMID 9782097. 
  2. ↑ "Tissue expression of HDAC2 - Summary - The Human Protein Atlas". https://www.proteinatlas.org/ENSG00000196591-HDAC2/tissue. 
  3. ↑ "Erasers of histone acetylation: the histone deacetylase enzymes". Cold Spring Harbor Perspectives in Biology 6 (4): a018713. April 2014. doi:10.1101/cshperspect.a018713. PMID 24691964. 
  4. ↑ 4.0 4.1 4.2 "Regulation of acetylation of histone deacetylase 2 by p300/CBP-associated factor/histone deacetylase 5 in the development of cardiac hypertrophy". Circulation Research 114 (7): 1133–1143. March 2014. doi:10.1161/CIRCRESAHA.114.303429. PMID 24526703. 
  5. ↑ 5.0 5.1 "Molecular dynamics and quantum chemistry-based approaches to identify isoform selective HDAC2 inhibitor - a novel target to prevent Alzheimer's disease". Journal of Receptor and Signal Transduction Research 38 (3): 266–278. June 2018. doi:10.1080/10799893.2018.1476541. PMID 29932788. 
  6. ↑ 6.0 6.1 "Upregulation of histone deacetylase 2 in laser capture nigral microglia in Parkinson's disease". Neurobiology of Aging 68: 134–141. August 2018. doi:10.1016/j.neurobiolaging.2018.02.018. PMID 29803514. 
  7. ↑ "Genome-wide characterization of lncRNAs in acute myeloid leukemia". Briefings in Bioinformatics 19 (4): 627–635. July 2018. doi:10.1093/bib/bbx007. PMID 28203711. 
  8. ↑ "HDAC2 depletion promotes osteosarcoma's stemness both in vitro and in vivo: a study on a putative new target for CSCs directed therapy". Journal of Experimental & Clinical Cancer Research 37 (1): 296. December 2018. doi:10.1186/s13046-018-0978-x. PMID 30509303. 
  9. ↑ "MicroRNA-31 Function as a Suppressor Was Regulated by Epigenetic Mechanisms in Gastric Cancer". BioMed Research International 2017: 5348490. 2017. doi:10.1155/2017/5348490. PMID 29333444. 
  10. ↑ "Structure, mechanism, and inhibition of histone deacetylases and related metalloenzymes". Current Opinion in Structural Biology 21 (6): 735–743. December 2011. doi:10.1016/j.sbi.2011.08.004. PMID 21872466. 
  11. ↑ "Exploration of the HDAC2 foot pocket: Synthesis and SAR of substituted N-(2-aminophenyl)benzamides". Bioorganic & Medicinal Chemistry Letters 20 (10): 3142–3145. May 2010. doi:10.1016/j.bmcl.2010.03.091. PMID 20392638. 
  12. ↑ "Entrez Gene: HDAC2 histone deacetylase 2". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3066. 
  13. ↑ "Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3 beta activity". Nature Medicine 13 (3): 324–331. March 2007. doi:10.1038/nm1552. PMID 17322895. 
  14. ↑ "Gene expression levels assessed by CA1 pyramidal neuron and regional hippocampal dissections in Alzheimer's disease". Neurobiology of Disease 45 (1): 99–107. January 2012. doi:10.1016/j.nbd.2011.07.013. PMID 21821124. 
  15. ↑ "c-Abl stabilizes HDAC2 levels by tyrosine phosphorylation repressing neuronal gene expression in Alzheimer's disease". Molecular Cell 56 (1): 163–173. October 2014. doi:10.1016/j.molcel.2014.08.013. PMID 25219501. 
  16. ↑ "HDAC2 Facilitates Pancreatic Cancer Metastasis". Cancer Research 82 (4): 695–707. February 2022. doi:10.1158/0008-5472.CAN-20-3209. PMID 34903606. 
  17. ↑ "Histone Deacetylase 2 Is a Component of Influenza A Virus-Induced Host Antiviral Response". Frontiers in Microbiology 8: 1315. 2017. doi:10.3389/fmicb.2017.01315. PMID 28769891. 
  18. ↑ 18.0 18.1 "Molecular association between ATR and two components of the nucleosome remodeling and deacetylating complex, HDAC2 and CHD4". Biochemistry 38 (44): 14711–14717. November 1999. doi:10.1021/bi991614n. PMID 10545197. 
  19. ↑ 19.0 19.1 19.2 19.3 "WD repeat-containing mitotic checkpoint proteins act as transcriptional repressors during interphase". FEBS Letters 575 (1–3): 23–29. September 2004. doi:10.1016/j.febslet.2004.07.089. PMID 15388328. 
  20. ↑ 20.0 20.1 20.2 20.3 20.4 20.5 20.6 20.7 20.8 20.9 "A candidate X-linked mental retardation gene is a component of a new family of histone deacetylase-containing complexes". The Journal of Biological Chemistry 278 (9): 7234–7239. February 2003. doi:10.1074/jbc.M208992200. PMID 12493763. 
  21. ↑ 21.0 21.1 21.2 21.3 21.4 "Chromatin deacetylation by an ATP-dependent nucleosome remodelling complex". Nature 395 (6705): 917–921. October 1998. doi:10.1038/27699. PMID 9804427. Bibcode: 1998Natur.395..917T. 
  22. ↑ 22.0 22.1 "A chromatin remodelling complex that loads cohesin onto human chromosomes". Nature 418 (6901): 994–998. August 2002. doi:10.1038/nature01024. PMID 12198550. Bibcode: 2002Natur.418..994H. 
  23. ↑ "DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci". Nature Genetics 25 (3): 269–277. July 2000. doi:10.1038/77023. PMID 10888872. 
  24. ↑ 24.0 24.1 24.2 "Transcriptional repression mediated by the human polycomb-group protein EED involves histone deacetylation". Nature Genetics 23 (4): 474–478. December 1999. doi:10.1038/70602. PMID 10581039. 
  25. ↑ "The FK506-binding protein 25 functionally associates with histone deacetylases and with transcription factor YY1". The EMBO Journal 20 (17): 4814–4825. September 2001. doi:10.1093/emboj/20.17.4814. PMID 11532945. 
  26. ↑ "Three-way control of fetal heart-cell proliferation could help regenerate cardiac cells". October 7, 2010. http://www.physorg.com/news205686730.html. 
  27. ↑ "Histone deacetylase 3 binds to and regulates the multifunctional transcription factor TFII-I". The Journal of Biological Chemistry 278 (3): 1841–1847. January 2003. doi:10.1074/jbc.M206528200. PMID 12393887. 
  28. ↑ 28.0 28.1 "Isolation and characterization of a novel class II histone deacetylase, HDAC10". The Journal of Biological Chemistry 277 (8): 6656–6666. February 2002. doi:10.1074/jbc.M108055200. PMID 11739383. 
  29. ↑ 29.0 29.1 29.2 "The metastasis-associated proteins 1 and 2 form distinct protein complexes with histone deacetylase activity". The Journal of Biological Chemistry 278 (43): 42560–42568. October 2003. doi:10.1074/jbc.M302955200. PMID 12920132. 
  30. ↑ 30.0 30.1 30.2 30.3 "A core-BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes". Proceedings of the National Academy of Sciences of the United States of America 99 (11): 7420–7425. May 2002. doi:10.1073/pnas.112008599. PMID 12032298. Bibcode: 2002PNAS...99.7420H. 
  31. ↑ 31.0 31.1 "Human class I histone deacetylase complexes show enhanced catalytic activity in the presence of ATP and co-immunoprecipitate with the ATP-dependent chaperone protein Hsp70". The Journal of Biological Chemistry 277 (11): 9590–9597. March 2002. doi:10.1074/jbc.M107942200. PMID 11777905. 
  32. ↑ "Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR". Molecular Cell 9 (1): 45–57. January 2002. doi:10.1016/s1097-2765(01)00429-4. PMID 11804585. 
  33. ↑ "Human HDAC7 histone deacetylase activity is associated with HDAC3 in vivo". The Journal of Biological Chemistry 276 (38): 35826–35835. September 2001. doi:10.1074/jbc.M104935200. PMID 11466315. 
  34. ↑ "The p65 (RelA) subunit of NF-kappaB interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 to negatively regulate gene expression". Molecular and Cellular Biology 21 (20): 7065–7077. October 2001. doi:10.1128/MCB.21.20.7065-7077.2001. PMID 11564889. 
  35. ↑ 35.0 35.1 35.2 35.3 "Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation". Genes & Development 13 (15): 1924–1935. August 1999. doi:10.1101/gad.13.15.1924. PMID 10444591. 
  36. ↑ "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. March 1998. doi:10.1073/pnas.95.7.3519. PMID 9520398. Bibcode: 1998PNAS...95.3519H. 
  37. ↑ "Histone deacetylases and SAP18, a novel polypeptide, are components of a human Sin3 complex". Cell 89 (3): 357–364. May 1997. doi:10.1016/s0092-8674(00)80216-0. PMID 9150135. 
  38. ↑ "Human Sin3 deacetylase and trithorax-related Set1/Ash2 histone H3-K4 methyltransferase are tethered together selectively by the cell-proliferation factor HCF-1". Genes & Development 17 (7): 896–911. April 2003. doi:10.1101/gad.252103. PMID 12670868. 
  39. ↑ "Transcriptional repression of oestrogen receptor by metastasis-associated protein 1 corepressor". Nature Cell Biology 3 (1): 30–37. January 2001. doi:10.1038/35050532. PMID 11146623. 
  40. ↑ 40.0 40.1 "Histone deacetylases associated with the mSin3 corepressor mediate mad transcriptional repression". Cell 89 (3): 349–356. May 1997. doi:10.1016/s0092-8674(00)80215-9. PMID 9150134. 
  41. ↑ "The Mad1-Sin3B interaction involves a novel helical fold". Nature Structural Biology 7 (12): 1100–1104. December 2000. doi:10.1038/81944. PMID 11101889. 
  42. ↑ "Two highly related p66 proteins comprise a new family of potent transcriptional repressors interacting with MBD2 and MBD3". The Journal of Biological Chemistry 277 (43): 40958–40966. October 2002. doi:10.1074/jbc.M207467200. PMID 12183469. 
  43. ↑ "MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex". Nature Genetics 23 (1): 58–61. September 1999. doi:10.1038/12659. PMID 10471499. 
  44. ↑ "Characterization of BHC80 in BRAF-HDAC complex, involved in neuron-specific gene repression". Biochemical and Biophysical Research Communications 322 (2): 601–608. September 2004. doi:10.1016/j.bbrc.2004.07.163. PMID 15325272. 
  45. ↑ "The protein phosphatase-1 (PP1) regulator, nuclear inhibitor of PP1 (NIPP1), interacts with the polycomb group protein, embryonic ectoderm development (EED), and functions as a transcriptional repressor". The Journal of Biological Chemistry 278 (33): 30677–30685. August 2003. doi:10.1074/jbc.M302273200. PMID 12788942. 
  46. ↑ 46.0 46.1 "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. June 2003. doi:10.1016/s0960-0760(03)00230-9. PMID 12943729. https://zenodo.org/record/1260176. 
  47. ↑ 47.0 47.1 47.2 "Silencing of transcription of the human luteinizing hormone receptor gene by histone deacetylase-mSin3A complex". The Journal of Biological Chemistry 277 (36): 33431–33438. September 2002. doi:10.1074/jbc.M204417200. PMID 12091390. 
  48. ↑ "CoREST is an integral component of the CoREST- human histone deacetylase complex". Proceedings of the National Academy of Sciences of the United States of America 98 (4): 1454–1458. February 2001. doi:10.1073/pnas.98.4.1454. PMID 11171972. Bibcode: 2001PNAS...98.1454Y. 
  49. ↑ "Post-activation turn-off of NF-kappa B-dependent transcription is regulated by acetylation of p65". The Journal of Biological Chemistry 278 (4): 2758–2766. January 2003. doi:10.1074/jbc.M209572200. PMID 12419806. 
  50. ↑ "Histone deacetylases augment cytokine induction of the iNOS gene". Journal of the American Society of Nephrology 13 (8): 2009–2017. August 2002. doi:10.1097/01.asn.0000024253.59665.f1. PMID 12138131. 
  51. ↑ "RBP1 recruits both histone deacetylase-dependent and -independent repression activities to retinoblastoma family proteins". Molecular and Cellular Biology 19 (10): 6632–6641. October 1999. doi:10.1128/mcb.19.10.6632. PMID 10490602. 
  52. ↑ "SAP30, a novel protein conserved between human and yeast, is a component of a histone deacetylase complex". Molecular Cell 1 (7): 1021–1031. June 1998. doi:10.1016/s1097-2765(00)80102-1. PMID 9651585. 
  53. ↑ "Role of the Sin3-histone deacetylase complex in growth regulation by the candidate tumor suppressor p33(ING1)". Molecular and Cellular Biology 22 (3): 835–848. February 2002. doi:10.1128/mcb.22.3.835-848.2002. PMID 11784859. 
  54. ↑ "Identification and characterization of three new components of the mSin3A corepressor complex". Molecular and Cellular Biology 23 (10): 3456–3467. May 2003. doi:10.1128/mcb.23.10.3456-3467.2003. PMID 12724404. 
  55. ↑ "An ERG (ets-related gene)-associated histone methyltransferase interacts with histone deacetylases 1/2 and transcription co-repressors mSin3A/B". The Biochemical Journal 369 (Pt 3): 651–657. February 2003. doi:10.1042/BJ20020854. PMID 12398767. 
  56. ↑ "A role for SKIP in EBNA2 activation of CBF1-repressed promoters". Journal of Virology 74 (4): 1939–1947. February 2000. doi:10.1128/jvi.74.4.1939-1947.2000. PMID 10644367. 
  57. ↑ "Functional and physical interaction between the histone methyl transferase Suv39H1 and histone deacetylases". Nucleic Acids Research 30 (2): 475–481. January 2002. doi:10.1093/nar/30.2.475. PMID 11788710. 
  58. ↑ 58.0 58.1 "Sp1 and Sp3 recruit histone deacetylase to repress transcription of human telomerase reverse transcriptase (hTERT) promoter in normal human somatic cells". The Journal of Biological Chemistry 277 (41): 38230–38238. October 2002. doi:10.1074/jbc.M206064200. PMID 12151407. 
  59. ↑ 59.0 59.1 "The transcriptional repressor Sp3 is associated with CK2-phosphorylated histone deacetylase 2". The Journal of Biological Chemistry 277 (39): 35783–35786. September 2002. doi:10.1074/jbc.C200378200. PMID 12176973. 
  60. ↑ "Histone deacetylase interacts directly with DNA topoisomerase II". Nature Genetics 26 (3): 349–353. November 2000. doi:10.1038/81671. PMID 11062478. 
  61. ↑ "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. October 1997. doi:10.1074/jbc.272.44.28001. PMID 9346952. 
  62. ↑ "Regulation of transcription factor YY1 by acetylation and deacetylation". Molecular and Cellular Biology 21 (17): 5979–5991. September 2001. doi:10.1128/mcb.21.17.5979-5991.2001. PMID 11486036. 
  63. ↑ "Yeast two-hybrid cloning of a novel zinc finger protein that interacts with the multifunctional transcription factor YY1". Nucleic Acids Research 25 (4): 843–849. February 1997. doi:10.1093/nar/25.4.843. PMID 9016636. 

Further reading

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