HDAC6 explained

Histone deacetylase 6 is an enzyme that in humans is encoded by the HDAC6 gene.^{[1] [2]} HDAC6 has emerged as a highly promising candidate to selectively inhibit as a therapeutic strategy to combat several types of cancer and neurodegenerative disorders.^[3]

Function

Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alters chromatin structure and affects transcription. The protein encoded by this gene belongs to class II of the histone deacetylase/acuc/apha family. It contains an internal duplication of two catalytic domains that appear to function independently of each other. This protein possesses histone deacetylase activity and represses transcription.^[4]

It retracts the cilium of the cell, which is necessary prior to mitosis.^[5]

HDAC encourages cell motility and catalyzes α-tubulin deacetylation.^[6] As a result the enzyme encourages cancer cell metastasis.^[7]

HDAC6 affects transcription and translation by regulating heat-shock protein 90 (Hsp90).

HDAC6 is required in the formation of stress granule (SG) proteins and is instrumental in SG formation; pharmacological inhibition or genetic removal of HDAC6 abolished SG formation.

HDAC6 bonds with high affinity to ubiquitinated proteins.^[8]

HDAC6 is involved in leptin sensitivity.^[9]

HDAC6 deacetylates tyrosine residue T178 on TAK1.^[10]

Clinical relevance

Mutations in this gene have been associated to Alzheimer's disease.^[11]

Over expression of this protein correlates with tumorigenesis and cell survival. HDAC6 also encourages metastasis of cancer cells.

Since HDAC6 is dysregulated and/or implicated in several cancers and neurodegenerative disorders, pharmacological inhibition of this specific enzyme holds great therapeutic potential and could also limit side effects associated with pan-inhibitors of multiple HDAC enzymes.^[3] Selective inhibition of HDAC6 as a strategy to treat cancers is however also subject of debate, since some HDAC6 inhibitors exhibited anti-tumor activity in vitro and in vivo only when administered in high concentrations, which also produced off-target effects. The findings suggest that further study is needed to clarify data on anti-cancer effects of selective HDAC6 inhibitors.^[12]

Interactions

HDAC6 has been shown to interact with HDAC11^[13] and Zinc finger and BTB domain-containing protein 16.^[14]

HDAC6 interacts with SG (Stress granule) protein G3BP1.

See also

• Histone deacetylase

Further reading

• Pazin MJ, Kadonaga JT . What's up and down with histone deacetylation and transcription? . Cell . 89 . 3 . 325–328 . May 1997 . 9150131 . 10.1016/S0092-8674(00)80211-1 . 11488594 . free .
• Wolffe AP . Transcriptional control. Sinful repression . Nature . 387 . 6628 . 16–17 . May 1997 . 9139815 . 10.1038/387016a0 . 29803420 . free .
• Huynh KD, Fischle W, Verdin E, Bardwell VJ . BCoR, a novel corepressor involved in BCL-6 repression . Genes & Development . 14 . 14 . 1810–1823 . July 2000 . 10898795 . 316791 . 10.1101/gad.14.14.1810 .
• Mahlknecht U, Schnittger S, Landgraf F, Schoch C, Ottmann OG, Hiddemann W, Hoelzer D . Assignment of the human histone deacetylase 6 gene (HDAC6) to X chromosome p11.23 by in situ hybridization . Cytogenetics and Cell Genetics . 93 . 1–2 . 135–136 . 2001 . 11474198 . 10.1159/000056967 . 41821644 .
• Kao HY, Lee CH, Komarov A, Han CC, Evans RM . Isolation and characterization of mammalian HDAC10, a novel histone deacetylase . The Journal of Biological Chemistry . 277 . 1 . 187–193 . January 2002 . 11677242 . 10.1074/jbc.M108931200 . free .
• Seigneurin-Berny D, Verdel A, Curtet S, Lemercier C, Garin J, Rousseaux S, Khochbin S . Identification of components of the murine histone deacetylase 6 complex: link between acetylation and ubiquitination signaling pathways . Molecular and Cellular Biology . 21 . 23 . 8035–8044 . December 2001 . 11689694 . 99970 . 10.1128/MCB.21.23.8035-8044.2001 .
• Tong JJ, Liu J, Bertos NR, Yang XJ . Identification of HDAC10, a novel class II human histone deacetylase containing a leucine-rich domain . Nucleic Acids Research . 30 . 5 . 1114–1123 . March 2002 . 11861901 . 101247 . 10.1093/nar/30.5.1114 .
• Gao L, Cueto MA, Asselbergs F, Atadja P . Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family . The Journal of Biological Chemistry . 277 . 28 . 25748–25755 . July 2002 . 11948178 . 10.1074/jbc.M111871200 . free .
• Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A, Yoshida M, Wang XF, Yao TP . 6 . HDAC6 is a microtubule-associated deacetylase . Nature . 417 . 6887 . 455–458 . May 2002 . 12024216 . 10.1038/417455a . 4373254 . 2002Natur.417..455H .
• Kirsh O, Seeler JS, Pichler A, Gast A, Müller S, Miska E, Mathieu M, Harel-Bellan A, Kouzarides T, Melchior F, Dejean A . 6 . The SUMO E3 ligase RanBP2 promotes modification of the HDAC4 deacetylase . The EMBO Journal . 21 . 11 . 2682–2691 . June 2002 . 12032081 . 125385 . 10.1093/emboj/21.11.2682 .
• Hook SS, Orian A, Cowley SM, Eisenman RN . Histone deacetylase 6 binds polyubiquitin through its zinc finger (PAZ domain) and copurifies with deubiquitinating enzymes . Proceedings of the National Academy of Sciences of the United States of America . 99 . 21 . 13425–13430 . October 2002 . 12354939 . 129689 . 10.1073/pnas.172511699 . free . 2002PNAS...9913425H .
• Westendorf JJ, Zaidi SK, Cascino JE, Kahler R, van Wijnen AJ, Lian JB, Yoshida M, Stein GS, Li X . 6 . Runx2 (Cbfa1, AML-3) interacts with histone deacetylase 6 and represses the p21(CIP1/WAF1) promoter . Molecular and Cellular Biology . 22 . 22 . 7982–7992 . November 2002 . 12391164 . 134736 . 10.1128/MCB.22.22.7982-7992.2002 .
• North BJ, Marshall BL, Borra MT, Denu JM, Verdin E . The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase . Molecular Cell . 11 . 2 . 437–444 . February 2003 . 12620231 . 10.1016/S1097-2765(03)00038-8 . free .
• Voelter-Mahlknecht S, Mahlknecht U . Cloning and structural characterization of the human histone deacetylase 6 gene . International Journal of Molecular Medicine . 12 . 1 . 87–93 . July 2003 . 12792815 . 10.3892/ijmm.12.1.87 .
• Brush MH, Guardiola A, Connor JH, Yao TP, Shenolikar S . Deactylase inhibitors disrupt cellular complexes containing protein phosphatases and deacetylases . The Journal of Biological Chemistry . 279 . 9 . 7685–7691 . February 2004 . 14670976 . 10.1074/jbc.M310997200 . free .
• Pandey UB, Batlevi Y, Baehrecke EH, Taylor JP . HDAC6 at the intersection of autophagy, the ubiquitin-proteasome system and neurodegeneration . Autophagy . 3 . 6 . 643–645 . Nov–Dec 2007 . 17912024 . 10.4161/auto.5050 . free .
• Pandey UB, Nie Z, Batlevi Y, McCray BA, Ritson GP, Nedelsky NB, Schwartz SL, DiProspero NA, Knight MA, Schuldiner O, Padmanabhan R, Hild M, Berry DL, Garza D, Hubbert CC, Yao TP, Baehrecke EH, Taylor JP . 6 . HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS . Nature . 447 . 7146 . 859–863 . June 2007 . 17568747 . 10.1038/nature05853 . 4365061 . 2007Natur.447..860P .

Notes and References

1. Grozinger CM, Hassig CA, Schreiber SL . Three proteins define a class of human histone deacetylases related to yeast Hda1p . Proceedings of the National Academy of Sciences of the United States of America . 96 . 9 . 4868–4873 . April 1999 . 10220385 . 21783 . 10.1073/pnas.96.9.4868 . free . 1999PNAS...96.4868G .
2. Nagase T, Ishikawa K, Suyama M, Kikuno R, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O . 6 . Prediction of the coding sequences of unidentified human genes. XII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro . DNA Research . 5 . 6 . 355–364 . December 1998 . 10048485 . 10.1093/dnares/5.6.355 . free .
3. Geurs S, Clarisse D, Baele F, Franceus J, Desmet T, De Bosscher K, D'hooghe M . Identification of mercaptoacetamide-based HDAC6 inhibitors via a lean inhibitor strategy: screening, synthesis, and biological evaluation . Chemical Communications . 58 . 42 . 6239–6242 . May 2022 . 35510683 . 10.1039/D2CC01550A . 248527466 . 1854/LU-8752799 . free .
4. Web site: Entrez Gene: HDAC6 histone deacetylase 6.
5. Krishnamurthy K, Wang G, Silva J, Condie BG, Bieberich E . Ceramide regulates atypical PKCzeta/lambda-mediated cell polarity in primitive ectoderm cells. A novel function of sphingolipids in morphogenesis . The Journal of Biological Chemistry . 282 . 5 . 3379–3390 . February 2007 . 17105725 . 10.1074/jbc.M607779200 . free .
6. Gao YS, Hubbert CC, Lu J, Lee YS, Lee JY, Yao TP . Histone deacetylase 6 regulates growth factor-induced actin remodeling and endocytosis . Molecular and Cellular Biology . 27 . 24 . 8637–8647 . December 2007 . 17938201 . 2169396 . 10.1128/MCB.00393-07 .
7. Aldana-Masangkay GI, Sakamoto KM . The role of HDAC6 in cancer . Journal of Biomedicine & Biotechnology . 2011 . 875824 . 2011 . 21076528 . 2975074 . 10.1155/2011/875824 . free .
8. Kwon S, Zhang Y, Matthias P . The deacetylase HDAC6 is a novel critical component of stress granules involved in the stress response . Genes & Development . 21 . 24 . 3381–3394 . December 2007 . 18079183 . 2113037 . 10.1101/gad.461107 .
9. Web site: Lavars N. 2022-01-18. Targeting an enzyme in fat cells drives rapid weight loss in obese mice. 2022-01-18. New Atlas. en-US.
10. Xu G, Niu L, Wang Y, Yang G, Zhu X, Yao Y, Zhao G, Wang S, Li H . 6 . HDAC6-dependent deacetylation of TAK1 enhances sIL-6R release to promote macrophage M2 polarization in colon cancer . Cell Death & Disease . 13 . 10 . 888 . October 2022 . 36270986 . 9587286 . 10.1038/s41419-022-05335-1 .
11. Cook C, Gendron TF, Scheffel K, Carlomagno Y, Dunmore J, DeTure M, Petrucelli L . Loss of HDAC6, a novel CHIP substrate, alleviates abnormal tau accumulation . Human Molecular Genetics . 21 . 13 . 2936–2945 . July 2012 . 22492994 . 3373241 . 10.1093/hmg/dds125 .
12. Depetter Y, Geurs S, De Vreese R, Goethals S, Vandoorn E, Laevens A, Steenbrugge J, Meyer E, de Tullio P, Bracke M, D'hooghe M, De Wever O . 6 . Selective pharmacological inhibitors of HDAC6 reveal biochemical activity but functional tolerance in cancer models . International Journal of Cancer . 145 . 3 . 735–747 . August 2019 . 30694564 . 10.1002/ijc.32169 . free .
13. Gao L, Cueto MA, Asselbergs F, Atadja P . Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family . The Journal of Biological Chemistry . 277 . 28 . 25748–25755 . July 2002 . 11948178 . 10.1074/jbc.M111871200 . free .
14. Chauchereau A, Mathieu M, de Saintignon J, Ferreira R, Pritchard LL, Mishal Z, Dejean A, Harel-Bellan A . 6 . HDAC4 mediates transcriptional repression by the acute promyelocytic leukaemia-associated protein PLZF . Oncogene . 23 . 54 . 8777–8784 . November 2004 . 15467736 . 10.1038/sj.onc.1208128 . free .