HDAC6

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

HDAC6
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3C5K, 3GV4, 3PHD, 5EDU, 5KH7
Identifiers
Aliases	HDAC6, CPBHM, HD6, PPP1R90, JM21, histone deacetylase 6
External IDs	OMIM: 300272; MGI: 1333752; HomoloGene: 31353; GeneCards: HDAC6; OMA:HDAC6 - orthologs
Gene location (Human) Chr. X chromosome (human) Band Xp11.23 Start 48,801,377 bp End 48,824,982 bp
Gene location (Mouse) Chr. X chromosome (mouse) Band X A1.1|X 3.58 cM Start 7,796,359 bp End 7,814,128 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right hemisphere of cerebellum anterior pituitary right lobe of liver right testis left testis body of uterus right ovary left ovary ventricular zone ganglionic eminence Top expressed in entorhinal cortex perirhinal cortex islet of Langerhans yolk sac central gray substance of midbrain CA3 field epiblast medullary collecting duct dorsomedial hypothalamic nucleus choroid plexus of fourth ventricle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function histone deacetylase binding misfolded protein binding metal ion binding enzyme binding NAD-dependent histone deacetylase activity (H3-K14 specific) beta-catenin binding zinc ion binding polyubiquitin modification-dependent protein binding protein binding tau protein binding dynein complex binding Hsp90 protein binding histone deacetylase activity microtubule binding alpha-tubulin binding ubiquitin binding beta-tubulin binding actin binding hydrolase activity ubiquitin protein ligase binding tubulin deacetylase activity RNA polymerase II cis-regulatory region sequence-specific DNA binding protein deacetylase activity acetylspermidine deacetylase activity Cellular component cytosol perinuclear region of cytoplasm caveola microtubule nucleus multivesicular body cell projection microtubule associated complex aggresome dynein complex histone deacetylase complex perikaryon axon inclusion body dendrite cell leading edge cytoplasmic microtubule cell body neuron projection nucleoplasm cytoplasm protein-containing complex Biological process Hsp90 deacetylation protein quality control for misfolded or incompletely synthesized proteins response to organic substance cellular response to topologically incorrect protein tubulin deacetylation regulation of establishment of protein localization ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway response to growth factor intracellular protein transport aggresome assembly negative regulation of proteolysis histone H3 deacetylation positive regulation of signal transduction peptidyl-lysine deacetylation response to misfolded protein regulation of transcription, DNA-templated regulation of protein stability ubiquitin-dependent protein catabolic process mitochondrion localization positive regulation of epithelial cell migration regulation of fat cell differentiation transcription, DNA-templated regulation of autophagy of mitochondrion polyubiquitinated misfolded protein transport response to toxic substance positive regulation of hydrogen peroxide-mediated programmed cell death regulation of microtubule-based movement regulation of signaling receptor activity protein polyubiquitination protein deacetylation negative regulation of hydrogen peroxide metabolic process regulation of autophagy negative regulation of oxidoreductase activity regulation of androgen receptor signaling pathway negative regulation of transcription, DNA-templated cellular response to misfolded protein positive regulation of chaperone-mediated protein complex assembly regulation of gene expression, epigenetic negative regulation of protein-containing complex disassembly autophagy negative regulation of microtubule depolymerization lysosome localization histone deacetylation cellular response to hydrogen peroxide collateral sprouting dendritic spine morphogenesis cilium assembly regulation of macroautophagy parkin-mediated stimulation of mitophagy in response to mitochondrial depolarization positive regulation of mitophagy in response to mitochondrial depolarization chromatin organization positive regulation of protein oligomerization protein-containing complex disassembly positive regulation of peptidyl-serine phosphorylation polyamine deacetylation spermidine deacetylation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 10013 15185 Ensembl ENSG00000094631 ENSMUSG00000031161 UniProt Q9UBN7 Q9Z2V5 RefSeq (mRNA) NM_006044 NM_001321225 NM_001321226 NM_001321227 NM_001321228 NM_001321229 NM_001321230 NM_001321231 NM_001130416 NM_010413 RefSeq (protein) NP_001308154 NP_001308155 NP_001308156 NP_001308157 NP_001308158 NP_001308159 NP_001308160 NP_006035 NP_001123888 NP_034543 Location (UCSC) Chr X: 48.8 – 48.82 Mb Chr X: 7.8 – 7.81 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

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.

It retracts the cilium of the cell, which is necessary prior to mitosis.

HDAC encourages cell motility and catalyzes α-tubulin deacetylation. As a result the enzyme encourages cancer cell metastasis.

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.

HDAC6 is involved in leptin sensitivity.

HDAC6 deacetylates tyrosine residue T178 on TAK1.

Clinical relevance

Mutations in this gene have been associated to Alzheimer's disease.

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. 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.

Interactions

HDAC6 has been shown to interact with HDAC11 and Zinc finger and BTB domain-containing protein 16.

HDAC6 interacts with SG (Stress granule) protein G3BP1.

See also

• Histone deacetylase

Further reading

• Pazin MJ, Kadonaga JT (May 1997). "What's up and down with histone deacetylation and transcription?". Cell. 89 (3): 325–328. doi:10.1016/S0092-8674(00)80211-1. PMID 9150131. S2CID 11488594.
• Wolffe AP (May 1997). "Transcriptional control. Sinful repression". Nature. 387 (6628): 16–17. doi:10.1038/387016a0. PMID 9139815. S2CID 29803420.
• Huynh KD, Fischle W, Verdin E, Bardwell VJ (July 2000). "BCoR, a novel corepressor involved in BCL-6 repression". Genes & Development. 14 (14): 1810–1823. doi:10.1101/gad.14.14.1810. PMC 316791. PMID 10898795.
• Mahlknecht U, Schnittger S, Landgraf F, Schoch C, Ottmann OG, Hiddemann W, Hoelzer D (2001). "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. doi:10.1159/000056967. PMID 11474198. S2CID 41821644.
• Kao HY, Lee CH, Komarov A, Han CC, Evans RM (January 2002). "Isolation and characterization of mammalian HDAC10, a novel histone deacetylase". The Journal of Biological Chemistry. 277 (1): 187–193. doi:10.1074/jbc.M108931200. PMID 11677242.
• Seigneurin-Berny D, Verdel A, Curtet S, Lemercier C, Garin J, Rousseaux S, Khochbin S (December 2001). "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. doi:10.1128/MCB.21.23.8035-8044.2001. PMC 99970. PMID 11689694.
• Tong JJ, Liu J, Bertos NR, Yang XJ (March 2002). "Identification of HDAC10, a novel class II human histone deacetylase containing a leucine-rich domain". Nucleic Acids Research. 30 (5): 1114–1123. doi:10.1093/nar/30.5.1114. PMC 101247. PMID 11861901.
• Gao L, Cueto MA, Asselbergs F, Atadja P (July 2002). "Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family". The Journal of Biological Chemistry. 277 (28): 25748–25755. doi:10.1074/jbc.M111871200. PMID 11948178.
• Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A, et al. (May 2002). "HDAC6 is a microtubule-associated deacetylase". Nature. 417 (6887): 455–458. Bibcode:2002Natur.417..455H. doi:10.1038/417455a. PMID 12024216. S2CID 4373254.
• Kirsh O, Seeler JS, Pichler A, Gast A, Müller S, Miska E, et al. (June 2002). "The SUMO E3 ligase RanBP2 promotes modification of the HDAC4 deacetylase". The EMBO Journal. 21 (11): 2682–2691. doi:10.1093/emboj/21.11.2682. PMC 125385. PMID 12032081.
• Hook SS, Orian A, Cowley SM, Eisenman RN (October 2002). "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. Bibcode:2002PNAS...9913425H. doi:10.1073/pnas.172511699. PMC 129689. PMID 12354939.
• Westendorf JJ, Zaidi SK, Cascino JE, Kahler R, van Wijnen AJ, Lian JB, et al. (November 2002). "Runx2 (Cbfa1, AML-3) interacts with histone deacetylase 6 and represses the p21(CIP1/WAF1) promoter". Molecular and Cellular Biology. 22 (22): 7982–7992. doi:10.1128/MCB.22.22.7982-7992.2002. PMC 134736. PMID 12391164.
• North BJ, Marshall BL, Borra MT, Denu JM, Verdin E (February 2003). "The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase". Molecular Cell. 11 (2): 437–444. doi:10.1016/S1097-2765(03)00038-8. PMID 12620231.
• Voelter-Mahlknecht S, Mahlknecht U (July 2003). "Cloning and structural characterization of the human histone deacetylase 6 gene". International Journal of Molecular Medicine. 12 (1): 87–93. doi:10.3892/ijmm.12.1.87. PMID 12792815.
• Brush MH, Guardiola A, Connor JH, Yao TP, Shenolikar S (February 2004). "Deactylase inhibitors disrupt cellular complexes containing protein phosphatases and deacetylases". The Journal of Biological Chemistry. 279 (9): 7685–7691. doi:10.1074/jbc.M310997200. PMID 14670976.
• Pandey UB, Batlevi Y, Baehrecke EH, Taylor JP (Nov–Dec 2007). "HDAC6 at the intersection of autophagy, the ubiquitin-proteasome system and neurodegeneration". Autophagy. 3 (6): 643–645. doi:10.4161/auto.5050. PMID 17912024.
• Pandey UB, Nie Z, Batlevi Y, McCray BA, Ritson GP, Nedelsky NB, et al. (June 2007). "HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS". Nature. 447 (7146): 859–863. Bibcode:2007Natur.447..860P. doi:10.1038/nature05853. PMID 17568747. S2CID 4365061.

External links

• HDAC6+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• HDAC6 human gene location in the UCSC Genome Browser.
• HDAC6 human gene details in the UCSC Genome Browser.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.