Biology:HDAC6
 Generic protein structure example |
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.[7]
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.[7]
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.[8]
See also
References
- ↑ "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. doi:10.1073/pnas.96.9.4868. PMID 10220385. Bibcode: 1999PNAS...96.4868G.
- ↑ "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. doi:10.1093/dnares/5.6.355. PMID 10048485.
- ↑ 3.0 3.1 "Identification of mercaptoacetamide-based HDAC6 inhibitors via a lean inhibitor strategy: screening, synthesis, and biological evaluation". Chemical Communications 58 (42): 6239–6242. May 2022. doi:10.1039/D2CC01550A. PMID 35510683. https://biblio.ugent.be/publication/8752799.
- ↑ "Entrez Gene: HDAC6 histone deacetylase 6". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10013.
- ↑ "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. doi:10.1074/jbc.M607779200. PMID 17105725.*Lay summary in: "Lipid helps cells find their way by keeping their 'antennae' up". July 9, 2012. http://phys.org/news/2012-07-lipid-cells-antennae.html.
- ↑ "Histone deacetylase 6 regulates growth factor-induced actin remodeling and endocytosis". Molecular and Cellular Biology 27 (24): 8637–8647. December 2007. doi:10.1128/MCB.00393-07. PMID 17938201.
- ↑ 7.0 7.1 7.2 "The role of HDAC6 in cancer". Journal of Biomedicine & Biotechnology 2011: 875824. 2011. doi:10.1155/2011/875824. PMID 21076528.
- ↑ 8.0 8.1 "The deacetylase HDAC6 is a novel critical component of stress granules involved in the stress response". Genes & Development 21 (24): 3381–3394. December 2007. doi:10.1101/gad.461107. PMID 18079183.
- ↑ "Targeting an enzyme in fat cells drives rapid weight loss in obese mice" (in en-US). 2022-01-18. https://newatlas.com/medical/enzyme-fat-cells-rapid-weight-loss-obese-mice/.
- ↑ "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. doi:10.1038/s41419-022-05335-1. PMID 36270986.
- ↑ "Loss of HDAC6, a novel CHIP substrate, alleviates abnormal tau accumulation". Human Molecular Genetics 21 (13): 2936–2945. July 2012. doi:10.1093/hmg/dds125. PMID 22492994.
- ↑ "Selective pharmacological inhibitors of HDAC6 reveal biochemical activity but functional tolerance in cancer models". International Journal of Cancer 145 (3): 735–747. August 2019. doi:10.1002/ijc.32169. PMID 30694564.
- ↑ "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. doi:10.1074/jbc.M111871200. PMID 11948178.
- ↑ "HDAC4 mediates transcriptional repression by the acute promyelocytic leukaemia-associated protein PLZF". Oncogene 23 (54): 8777–8784. November 2004. doi:10.1038/sj.onc.1208128. PMID 15467736.
Further reading
- "What's up and down with histone deacetylation and transcription?". Cell 89 (3): 325–328. May 1997. doi:10.1016/S0092-8674(00)80211-1. PMID 9150131.
- "Transcriptional control. Sinful repression". Nature 387 (6628): 16–17. May 1997. doi:10.1038/387016a0. PMID 9139815.
- "BCoR, a novel corepressor involved in BCL-6 repression". Genes & Development 14 (14): 1810–1823. July 2000. doi:10.1101/gad.14.14.1810. PMID 10898795.
- "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. doi:10.1159/000056967. PMID 11474198.
- "Isolation and characterization of mammalian HDAC10, a novel histone deacetylase". The Journal of Biological Chemistry 277 (1): 187–193. January 2002. doi:10.1074/jbc.M108931200. PMID 11677242.
- "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. doi:10.1128/MCB.21.23.8035-8044.2001. PMID 11689694.
- "Identification of HDAC10, a novel class II human histone deacetylase containing a leucine-rich domain". Nucleic Acids Research 30 (5): 1114–1123. March 2002. doi:10.1093/nar/30.5.1114. PMID 11861901.
- "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. doi:10.1074/jbc.M111871200. PMID 11948178.
- "HDAC6 is a microtubule-associated deacetylase". Nature 417 (6887): 455–458. May 2002. doi:10.1038/417455a. PMID 12024216. Bibcode: 2002Natur.417..455H.
- "The SUMO E3 ligase RanBP2 promotes modification of the HDAC4 deacetylase". The EMBO Journal 21 (11): 2682–2691. June 2002. doi:10.1093/emboj/21.11.2682. PMID 12032081.
- "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. doi:10.1073/pnas.172511699. PMID 12354939. Bibcode: 2002PNAS...9913425H.
- "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. doi:10.1128/MCB.22.22.7982-7992.2002. PMID 12391164.
- "The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase". Molecular Cell 11 (2): 437–444. February 2003. doi:10.1016/S1097-2765(03)00038-8. PMID 12620231.
- "Cloning and structural characterization of the human histone deacetylase 6 gene". International Journal of Molecular Medicine 12 (1): 87–93. July 2003. doi:10.3892/ijmm.12.1.87. PMID 12792815.
- "Deactylase inhibitors disrupt cellular complexes containing protein phosphatases and deacetylases". The Journal of Biological Chemistry 279 (9): 7685–7691. February 2004. doi:10.1074/jbc.M310997200. PMID 14670976.
- "HDAC6 at the intersection of autophagy, the ubiquitin-proteasome system and neurodegeneration". Autophagy 3 (6): 643–645. Nov–Dec 2007. doi:10.4161/auto.5050. PMID 17912024.
- "HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS". Nature 447 (7146): 859–863. June 2007. doi:10.1038/nature05853. PMID 17568747. Bibcode: 2007Natur.447..860P.
External links
- HDAC6+protein,+human at the US 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.
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