HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates

Boyault, Cyril; Zhang, Yu; Fritah, Sabrina; Caron, Cécile; Gilquin, Benoît; Kwon, So Hee; Garrido, Carmen; Yao, Tso‐Pang; Vourc’h, Claire; Matthias, Patrick; Khochbin, Saadi

doi:10.1101/gad.436407

Cited by 324 publications

(336 citation statements)

References 40 publications

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“…We next determined if HPOB inhibited HDAC6 ubiquitin-binding complex formation induced by the complex carbohydrate, trehalose. It has been shown that HDAC6 has a role in ubiquitin-bindingcomplex-forming aggresomes in the autophagic pathway of cell death (8,9,24,25). Trehalose induces aggresome formation and autophagy (26).…”

Section: Significancementioning

confidence: 99%

“…The reversible acetylation of Hsp90, a substrate of HDAC6, modulates its chaperone activity and, accordingly, the stability of survival and antiapoptotic factors, including epidermal growth factor receptor (EGFR), protein kinase AKT, proto-oncogene C-RAF, survivin, and other factors. HDAC6, through its ubiquitin-binding activity and interaction with other partner proteins, plays a role in the degradation of misfolded proteins by binding polyubiquitinated proteins and delivering them to the dynein and motor proteins for transport into aggresomes which are degraded by lysosomes (8)(9)(10). Thus, HDAC6 has multiple biological functions through deacetylasedependent and -independent mechanisms modulating many cellular pathways relevant to normal and tumor cell growth, migration, and death.…”

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confidence: 99%

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Development of a histone deacetylase 6 inhibitor and its biological effects

Lee

Mahendran

Yao

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

124

105

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Development of isoform-selective histone deacetylase (HDAC) inhibitors is important in elucidating the function of individual HDAC enzymes and their potential as therapeutic agents. Among the eleven zinc-dependent HDACs in humans, HDAC6 is structurally and functionally unique. Here, we show that a hydroxamic acid-based small-molecule N-hydroxy-4-(2-[(2-hydroxyethyl)(phenyl)amino]-2-oxoethyl)benzamide (HPOB) selectively inhibits HDAC6 catalytic activity in vivo and in vitro. HPOB causes growth inhibition of normal and transformed cells but does not induce cell death. HPOB enhances the effectiveness of DNA-damaging anticancer drugs in transformed cells but not normal cells. HPOB does not block the ubiquitin-binding activity of HDAC6. The HDAC6-selective inhibitor HPOB has therapeutic potential in combination therapy to enhance the potency of anticancer drugs.anticancer agents | epigenetics-based chemotherapy | drug discovery H istone deacetylase 6 (HDAC6) is unique among the eleven zinc-dependent HDACs in humans. HDAC6 is located in the cytoplasm, and it has two catalytic domains and an ubiquitinbinding domain at the C-terminal region (1-3). This study focused on the development of a HDAC6-selective inhibitor and its biological effects. The substrates of HDAC6 include nonhistone proteins such as α-tubulin, peroxiredoxin (PRX), cortactin, and heat shock protein 90 (Hsp90) but not histones (4-7). HDAC6 plays a key role in the regulation of microtubule dynamics including cell migration and cell-cell interactions. The reversible acetylation of Hsp90, a substrate of HDAC6, modulates its chaperone activity and, accordingly, the stability of survival and antiapoptotic factors, including epidermal growth factor receptor (EGFR), protein kinase AKT, proto-oncogene C-RAF, survivin, and other factors. HDAC6, through its ubiquitin-binding activity and interaction with other partner proteins, plays a role in the degradation of misfolded proteins by binding polyubiquitinated proteins and delivering them to the dynein and motor proteins for transport into aggresomes which are degraded by lysosomes (8-10). Thus, HDAC6 has multiple biological functions through deacetylasedependent and -independent mechanisms modulating many cellular pathways relevant to normal and tumor cell growth, migration, and death. HDAC6 is an attractive target for potential cancer treatment.There are several previous reports on the development of HDAC6-selective inhibitors (11)(12)(13)(14)(15). The most extensively studied is tubacin (16,17). Tubacin has non-drug-like qualities, high lipophilicity, and difficult synthesis and has proved to be more useful as a research tool rather than as a potential drug (18). We and others (12)(13)(14)(15)19) have developed HDAC6-selective inhibitors whose pharmacokinetics, toxicity, and efficacy make them potentially more useful than tubacin as therapeutic agents. ACY-1215, 2-(Diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide, a HDAC6-selective inhibitor, is currently being evaluated in clinical trial...

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Section: Significancementioning

confidence: 99%

mentioning

confidence: 99%

Development of a histone deacetylase 6 inhibitor and its biological effects

Lee

Mahendran

Yao

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

124

105

View full text Add to dashboard Cite

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“…The formation of aggresomes has been suggested to be a cytoprotective response that sequesters toxic misfolded proteins and facilitates their removal by autophagy, which concludes with lysosomal degradation. The formation and processing of aggresomes involve a variety of regulators, including E3 ubiquitin-protein ligase parkin, deubiquitinating enzymes such as ataxin-3 and ubiquilin-1, and histone deacetylase 6 [16][17][18].…”

Section: Spatial Quality Control and Its Links To Ageingmentioning

confidence: 99%

Spatial protein quality control and the evolution of lineage-specific ageing

Nyström

2011

Phil. Trans. R. Soc. B

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Propagation of a species requires periodic cell renewal to avoid clonal extinction. Sexual reproduction and the separation of germ cells from the soma provide a mechanism for such renewal, but are accompanied by an apparently mandatory ageing of the soma. Data obtained during the last decade suggest that a division of labour exists also between cells of vegetatively reproducing unicellular organisms, leading to the establishment of a soma-like and germ-like lineage with distinct fitness and longevity characteristics. This division of labour in both bacteria and yeast entails segregation of damaged and aggregated proteins such that the germ-like lineage is kept free of damage to the detriment of the soma-like lineage. In yeast, this spatial protein quality control (SQC) encompasses a CCT-chaperonin-dependent translocation and merging of cytotoxic protein aggregates. This process is regulated by Sir2, a protein deacetylase that modulates the rate of ageing in organisms ranging from yeast to worms and flies. Recent data also demonstrate that SQC is intimately integrated with the machinery establishing proper cell polarity and that this machinery is required for generating a soma-like and germ-like lineage in yeast. Deciphering the details of the SQC network may increase our understanding of the development of age-related protein folding disorders and shed light on the selective forces that paved the way for polarity and lineage-specific ageing to evolve.

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“…15,16). In the latent state, HSF1 resides in a multichaperone complex with HSP90 and histone deacetylase (HDAC) 6 (17). Following cellular insult by a plethora of diverse chemical and physiologic stresses, monomeric HSF1 is released from this repressive complex and undergoes a homotrimerization process and extensive phosphorylation that promotes its translocation into the nucleus.…”

Section: Introductionmentioning

confidence: 99%

mTOR Inhibition Potentiates HSP90 Inhibitor Activity via Cessation of HSP Synthesis

Acquaviva

Sang

et al. 2014

Molecular Cancer Research

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Because of their pleiotropic effects on critical oncoproteins, inhibitors of HSP90 represent a promising new class of therapeutic agents for the treatment of human cancer. However, pharmacologic inactivation of HSP90 subsequently triggers a heat shock response that may mitigate the full therapeutic benefit of these compounds. To overcome this limitation, a clinically feasible method was sought to block HSP synthesis induced by the potent HSP90 inhibitor ganetespib. An immunoassay screen of 322 late-stage or clinically approved drugs was performed to uncover compounds that could block upregulation of the stress-inducible HSP70 that results as a consequence of HSP90 blockade. Interestingly, inhibitors of the phosphoinositide 3-kinase (PI3K)/mTOR class counteracted ganetespibinduced HSP70 upregulation at both the gene and protein level by suppressing nuclear translocation of heat shock factor 1 (HSF1), the dominant transcription factor controlling cellular stress responses. This effect was conserved across multiple tumor types and was found to be regulated, in part, by mTOR-dependent translational activity. Pretreatment with cycloheximide, PI3K/mTOR inhibitor, or an inhibitor of eIF4E (a translation initiation factor and downstream effector of mTOR) all reduced ganetespib-mediated nuclear HSF1 accumulation, indicating that mTOR blockade confers a negative regulatory effect on HSF1 activity. Moreover, combined therapy regimens with mTOR or dual PI3K/mTOR inhibitors potentiated the antitumor efficacy of ganetespib in multiple in vivo models.

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HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates

Cited by 324 publications

References 40 publications

Development of a histone deacetylase 6 inhibitor and its biological effects

Development of a histone deacetylase 6 inhibitor and its biological effects

Spatial protein quality control and the evolution of lineage-specific ageing

mTOR Inhibition Potentiates HSP90 Inhibitor Activity via Cessation of HSP Synthesis

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