Cited by 414Histone Deacetylase Inhibitors ResearchUbiquitin and proteasome pathwaysMicrotubule and mitosis dynamics

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HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination

Boyault, C, Sadoul, K, Pabion, M, Khochbin, S·2007·Oncogene

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Abstract

Histone deacetylase 6 (HDAC6) is a unique enzyme with specific structural and functional features. It is actively or stably maintained in the cytoplasm and is the only member, within the histone deacetylase family, that harbors a full duplication of its deacetylase homology region followed by a specific ubiquitin-binding domain at the C-terminus end. Accordingly, this deacetylase functions at the heart of a cellular regulatory mechanism capable of coordinating various cellular functions largely relying on the microtubule network. Moreover, HDAC6 action as a regulator of the HSP90 chaperone activity adds to the multifunctionality of the protein, and allows us to propose a critical role for HDAC6 in mediating and coordinating various cellular events in response to different stressful stimuli.

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Background
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Background
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Background
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Background
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Background
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Background
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Background
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Hsp90
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Background
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“, heat-shock response), redox signaling, inflammation and intracellular trafficking (Boyault et al., 2007; Li et al., 2013; Richter-Landsberg and Leyk, 2013; Simoes-Pires et al., 2013; Ryu et al., 2017).”
Background
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Nawar, N., Bukhari, S., Adile, A., Suk, Y., Manaswiyoungkul, P., Toutah, K., Olaoye, O. O., Raouf, Y. S., Sedighi, A., Garcha, H. K., et al. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c01585 · Cited by 38
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Histone deacetylase inhibitors and a functional potent inhibitory effect on human uterine contractility
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Aggresome formation is regulated by RanBPM through an interaction with HDAC6
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“…by functioning as a key factor recruiting protein cargo to the dynein motor for transport into the aggresome and by regulating a cell response pathway involving the activation of a heat-shock response that helps the clearance of the aggregates (Boyault et al., 2007b; Kawaguchi et al., 2003).”
BackgroundMethod
Gene expression regulation by heat-shock proteins: the cardinal roles of HSF1 and Hsp90
Mazaira, G. I., Daneri-Becerra, C., Zgajnar, N. R., Lotufo, C. M., & Galigniana, M. D. (2017) · Biochemical Society Transactions · doi:10.1042/bst20170335 · Cited by 36
Hemap: An Interactive Online Resource for Characterizing Molecular Phenotypes across Hematologic Malignancies
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“Surprisingly, the HDAC expression pattern revealed cytosolic members ( HDAC6 and HDAC10 (62)) as resistance markers, while nuclear HDAC4 and HDAC9 correlated with sensitivity.”
Background
Inhibition of HDAC6 Attenuates Tumor Growth of Non-Small Cell Lung Cancer
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“We show that Notch1 receptor levels are regulated through the UPS by HDAC6 enzymatic function; inhibition of HDAC6 with small molecules tubacin and ACY1215 reduces total levels of Notch1 receptor.”
BackgroundInfluential
Inhibition of histone deacetylase 6 suppresses inflammatory responses and invasiveness of fibroblast-like-synoviocytes in inflammatory arthritis
Park, J. K., Shon, S. H., Yoo, H. J., Suh, D., Bae, D., Shin, J., Jun, J. H., Ha, N., Song, H., Choi, Y. I., et al. (2021) · Arthritis Research & Therapy · doi:10.1186/s13075-021-02561-4 · Cited by 35
“Therefore, the production and secretion of cytokines can be regulated by modifying the cytoskeleton, which controls intracellular transport and signaling [31].”
Background
Fam65b is important for formation of the HDAC6‐dysferlin protein complex during myogenic cell differentiation
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“HDAC6 is a cytoplasmic HDAC known for its role in cell migration, chemotaxis, and regulation of tubulin acetylation (14, 42, 43).”
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A novel histone deacetylase 6‐selective inhibitor suppresses synovial inflammation and joint destruction in a collagen antibody‐induced arthritis mouse model
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HDAC6 regulates NF-κB signalling to control chondrocyte IL-1-induced MMP and inflammatory gene expression
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Selective and Bioavailable HDAC6 2-(Difluoromethyl)-1,3,4-oxadiazole Substrate Inhibitors and Modeling of Their Bioactivation Mechanism
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HDAC6 inhibitor ACY-1215 enhances STAT1 acetylation to block PD-L1 for colorectal cancer immunotherapy
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“HDAC6 is the most widely studied class IIb HDAC, and its unique structure and cytoplasmic localization distinguish it from other members of the HDAC family [56].”
Background
A Novel Dual HDAC6 and Tubulin Inhibitor, MPT0B451, Displays Anti-tumor Ability in Human Cancer Cells in Vitro and in Vivo
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“In addition to its unique cytoplasmic localization, HDAC6 also specifically deacetylates α-tubulin, the most abundant microtubule component, as well as cortactin and Hsp90α rather than histone proteins (Hubbert et al., 2002; Boyault et al., 2007).”
Background
Histone deacetylase 8 is deregulated in urothelial cancer but not a target for efficient treatment
Lehmann, M., Hoffmann, M. J., Koch, A., Ulrich, S. M., Schulz, W. A., & Niegisch, G. (2014) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-014-0059-8 · Cited by 34
“HDAC6 influences the cytoskeleton and cell motility via deacetylation of α-tubulin and other cytoskeleton proteins [46].”
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Molecular Chaperone Hsp90 Regulates REV1-Mediated Mutagenesis
Pozo, F. M., Oda, T., Sekimoto, T., Murakumo, Y., Masutani, C., Hanaoka, F., & Yamashita, T. (2011) · Molecular and Cellular Biology · doi:10.1128/mcb.05117-11 · Cited by 34
“PARP-1 binds directly to PCNA, and HDAC6 binds directly to Ub (5, 11).”
Background
HDAC6 as a potential therapeutic target for peripheral nerve disorders
Prior, R. C., Helleputte, L. V., Klingl, Y. E., & Bosch, L. V. D. (2018) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2018.1541235 · Cited by 35
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HDAC6-dependent deacetylation of TAK1 enhances sIL-6R release to promote macrophage M2 polarization in colon cancer
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“In the past few decades, HDAC6 has been recognized as an important member of the HDAC family because it contains two deacetylase catalytic domains and is mainly located in the cytoplasm [39, 40].”
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Histone Deacetylase Inhibitors: Updated Studies in Various Epigenetic-Related Diseases
Zwergel, C., Stazi, G., Valente, S., & Mai, A. (2016) · Journal of Clinical Epigenetics · Cited by 32
Endothelial cell elongation and alignment in response to shear stress requires acetylation of microtubules
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Nitric oxide and histone deacetylases
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Chromatin‐remodelling proteins of the pea aphid, Acyrthosiphon pisum (Harris)
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The HDAC6 inhibitor AVS100 (SS208) induces a pro-inflammatory tumor microenvironment and potentiates immunotherapy
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“HSP90 is another known target of HDAC6 controlling the regulation of diverse cell signals and protein stability ( 4 ).”
HDAC6 and Ovarian Cancer
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Structure-Based Drug Designing Recommends HDAC6 Inhibitors To Attenuate Microtubule-Associated Tau-Pathogenesis
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Inhibition of Histone Deacetylase 6 by Tubastatin A Attenuates the Progress of Osteoarthritis via Improving Mitochondrial Function
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“HDAC6 is a cytoplasmic localized histone deacetylase that has deacetylase activity and ubiquitinated protein-binding ability.(17,27) The acetylation of tubulin caused by deacetylase activity of HDAC6 is of great significance for the regulation of the function of the microtubule system.”
Background
Non-histone substrates of histone deacetylases as potential therapeutic targets in epilepsy
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Unique Molecular Interaction with the Histone Deacetylase 6 Catalytic Tunnel: Crystallographic and Biological Characterization of a Model Chemotype
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Histone Deacetylase 6 and the Disease Mechanisms of α-Synucleinopathies
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Depression of mitochondrial metabolism by downregulation of cytoplasmic deacetylase, HDAC6
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“HDAC6 is a cytoplasmic deacetylase which has double deacetylase domains and an ubiquitin binding domain [1,2,20].”
Background
Protein aggregate formation in oligodendrocytes: tau and the cytoskeleton at the intersection of neuroprotection and neurodegeneration
Richter‐Landsberg, C. (2015) · Biological Chemistry · doi:10.1515/hsz-2015-0157 · Cited by 28
“This promotes the assembly of a microfilament network, which is necessary for the fusion of the autophagosome with the lysosome and facilitates substrate degradation (Boyault et al., 2007; Banreti et al., 2013).”
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Histone deacetylase in neuropathology
Gupta, R. V., Ambasta, R. K., & Kumar, P. (2020) · Advances in clinical chemistry · doi:10.1016/bs.acc.2020.09.004 · Cited by 28
Retracted: Silence of HDAC6 suppressed esophageal squamous cell carcinoma proliferation and migration by disrupting chaperone function of HSP90
Tao, H., Chen, Y., Sun, Z., Chen, H., & Chen, M. (2018) · Journal of Cellular Biochemistry · doi:10.1002/jcb.26841 · Cited by 27
“Unlike nuclear location of other HDAC familymembers, HDAC6 is a unique deacetylase for its cytoplasm localization and ability to deacetylate proteins other than histone.(4) Overexpression of HDAC6 was reported to be associated with cancer cell migration and invasion through deacetylating its substrate in several cance…”
Background
Retracted
MPT0G413, A Novel HDAC6-Selective Inhibitor, and Bortezomib Synergistically Exert Anti-tumor Activity in Multiple Myeloma Cells
Huang, F.-I., Wu, Y.-W., Sung, T.-Y., Liou, J., Lin, M., Pan, S., & Yang, C. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00249 · Cited by 26

Authors: Boyault, C., Sadoul, K., Pabion, M., & Khochbin, S.
Affiliations: Inserm (FR)
Corresponding author: Khochbin, S
ORCID: Boyault, C
Sadoul, K
Khochbin, S
Venue: Oncogene
Publisher: Springer Science and Business Media LLC
Published: 2007-08-13
Volume: 26
Issue: 37
Pages: 5468-5476
ISSN: 0950-9232 (ISSN-L)
1476-5594
DOI: 10.1038/sj.onc.1210614
OpenAlex: W2030185116
Cited by: 397
References: 85
Citations by year: 2026: 12 · 2025: 17 · 2024: 19 · 2023: 15 · 2022: 24 · 2021: 26 · 2020: 32 · 2019: 18 · 2018: 31 · 2017: 16 · 2016: 9 · 2015: 23 · 2014: 21 · 2013: 24 · 2012: 26
FWCI: 1.72
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Oncogene (publishedVersion)
PubMed (publishedVersion)
Funders: Institut National Du Cancer
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
Keywords: HDAC6, histone deacetylase, microtubule cytoskeleton, cytoskeleton, protein acetylation, ubiquitination, ubiquitin-binding domain, Hsp90 chaperone, signal transduction, stress response
MeSH terms: Acetylation, Animals, Cell Nucleus, Cytoskeleton, Enzyme Inhibitors, Histone Deacetylases, Humans, Protein Processing, Post-Translational, Signal Transduction, Protein Structure, Tertiary, Ubiquitin, Histone Deacetylase Inhibitors

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HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination

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