Inhibition of Histone Deacetylase 6 Acetylates and Disrupts the Chaperone Function of Heat Shock Protein 90

Bali, Purva; Pranpat, Michael; Bradner, James E.; Balasis, Maria E.; Fiskus, Warren; Guo, Fei; Rocha, Kathy; Kumaraswamy, S.; Boyapalle, Sandhya; Atadja, Peter; Seto, Edward; Bhalla, Kapil N.

doi:10.1074/jbc.c500186200

Cited by 731 publications

(747 citation statements)

References 38 publications

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“…A comparison of several other HDAC inhibitors currently in clinical development confirmed that panobinostat (LBH589) is also a highly potent inhibitor of both HDAC1 activity and tumour cell proliferation in vitro (Bali et al, 2005), while vorinostat (SAHA) showed lower potency towards both HDAC1 and tumour cell proliferation, which is in agreement with previous publications (Butler et al, 2000). The benzamide MS-275 did not inhibit HDAC1 enzyme activity up to 1 mM, and showed low antiproliferative potency.…”

Section: Resultssupporting

confidence: 90%

“…We evaluated the acetylation status in A2780 ovarian carcinoma cells of H3, which is acetylated through class I HDACs (Glaser et al, 2003), and tubulin, which is acetylated by the class II family member HDAC6 (Matsuyama et al, 2002;Zhang et al, 2003). Inhibition of HDAC6 also induces Hsp90 acetylation, resulting in Hsp70 induction and degradation of Hsp90-associated pro-survival and pro-proliferative client proteins such as c-raf (Bali et al, 2005).…”

Section: Resultsmentioning

confidence: 99%

“…Inhibition of the class IIb enzyme HDAC6, which is a tubulin and Hsp90 deacetylase, caused a-tubulin hyperacetylation and decreased cell motility, but did not affect cell-cycle progression Zhang et al, 2003). Although inhibition of class II HDAC enzymes does not result in antiproliferative activity in vitro, it may potentiate antitumoral effects of other anticancer agents such as radiation (through HDAC4) or proteasome inhibitors (through HDAC6) (Bali et al, 2005). The distinct biological roles of HDAC family members strongly suggest that the selectivity profile of HDAC inhibitors will have major consequences on their clinical activities.…”

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confidence: 99%

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R306465 is a novel potent inhibitor of class I histone deacetylases with broad-spectrum antitumoral activity against solid and haematological malignancies

Arts¹,

Angibaud²,

Marien³

et al. 2007

Br J Cancer

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R306465 is a novel hydroxamate-based histone deacetylase (HDAC) inhibitor with broad-spectrum antitumour activity against solid and haematological malignancies in preclinical models. R306465 was found to be a potent inhibitor of HDAC1 and -8 (class I) in vitro. It rapidly induced histone 3 (H3) acetylation and strongly upregulated expression of p21 waf1,cip1 , a downstream component of HDAC1 signalling, in A2780 ovarian carcinoma cells. R306465 showed class I HDAC isotype selectivity as evidenced by poor inhibition of HDAC6 (class IIb) confirmed by the absence of downregulation of Hsp90 chaperone c-raf protein expression and tubulin acetylation. This distinguished it from other HDAC inhibitors currently in clinical development that were either more potent towards HDAC6 (e.g. vorinostat) or had a broader HDAC inhibition spectrum (e.g. panobinostat). R306465 potently inhibited cell proliferation of all main solid tumour indications, including ovarian, lung, colon, breast and prostate cancer cell lines, with IC 50 values ranging from 30 to 300 nM. Haematological cell lines, including acute lymphoblastic leukaemia, acute myeloid leukaemia, chronic lymphoblastic leukaemia, chronic myeloid leukaemia, lymphoma and myeloma, were potently inhibited at a similar concentration range. R306465 induced apoptosis and inhibited angiogenesis in cell-based assays and had potent oral in vivo antitumoral activity in xenograft models. Once-daily oral administration of R306465 at well-tolerated doses inhibited the growth of A2780 ovarian, H460 lung and HCT116 colon carcinomas in immunodeficient mice. The high activity of R306465 in cell-based assays and in vivo after oral administration makes R306465 a promising novel antitumoral agent with potential applicability in a broad spectrum of human malignancies.

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Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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R306465 is a novel potent inhibitor of class I histone deacetylases with broad-spectrum antitumoral activity against solid and haematological malignancies

Arts¹,

Angibaud²,

Marien³

et al. 2007

Br J Cancer

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“…Of the known substrates of HDAC6, Hsp90 may be linked with the HDAC6-mediated regulation of mitochondrial metabolic activity. Inactivation of HDAC6 leads to hyperacetylation of Hsp90 and instability of its client proteins [6,7]. Interestingly, Kang et al have found that an abundant pool of Hsp90 localizes to mitochondria in various tumor cells and regulates mitochondrial integrity [21].…”

Section: Hdac6 Regulates Mitochondrial Metabolic Activity In the Cytomentioning

confidence: 99%

“…Early studies found that HDAC6-mediated a-tubulin deacetylation destabilizes dynamic microtubules [3] and promotes an increase in cell motility [4,5]. In addition to a-tubulin, several cytoplasmic proteins including Hsp90 [6,7], cortactin [8], b-catenin [9], peroxiredoxins I and II [10], and Ku70 [11] are regulated in a HDAC6-mediated deacetylation-dependent manner. Strong ubiquitin binding activity [12,13] further adds to the multifunctionality of HDAC6, enabling the regulation of many important processes including cell migration, cell stress response to the cytotoxic accumulation of protein aggregates, and immune synapse formation [1,2].…”

Section: Introductionmentioning

confidence: 99%

Depression of mitochondrial metabolism by downregulation of cytoplasmic deacetylase, HDAC6

et al. 2012

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a b s t r a c tMitochondria perform multiple functions critical to the maintenance of cellular homeostasis. Here we report that the downregulation of histone deacetylase 6 (HDAC6) causes a reduction in the net activity of mitochondrial enzymes, including respiratory complex II and citrate synthase. HDAC6 deacetylase and ubiquitin-binding activities were both required for recovery of reduced mitochondrial metabolic activity due to the loss of HDAC6. Hsp90, a substrate of HDAC6, localizes to mitochondria and partly mediates the regulation of mitochondrial metabolic activity by HDAC6. Our finding suggests that HDAC6 regulates mitochondrial metabolism and might serve as a cellular homeostasis surveillance factor.

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Histone Deacetylase Inhibitors: A Brief Overview Of Their Role And Medicinal Chemistry

Angibaud¹,

Emelen²,

Arts³

2010

Burger's Medicinal Chemistry and Drug Discovery

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Histone deacetylase s ( HDAC s) comprise a family of proteins that impact critical cellular processes through regulation of chromatin remodeling and gene transcription. HDACs have emerged as attractive targets for the development of new anticancer agents and a number of structurally diverse inhibitors of HDAC from natural or synthetic origin have been described in the literature. This chapter focuses on those having reached clinical phases. For each, synthesis pathway, in vitro properties and short clinical profiles are presented. Recent developments in medicinal chemistry of HDAC inhibition are also reported.

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Inhibition of Histone Deacetylase 6 Acetylates and Disrupts the Chaperone Function of Heat Shock Protein 90

Cited by 731 publications

References 38 publications

R306465 is a novel potent inhibitor of class I histone deacetylases with broad-spectrum antitumoral activity against solid and haematological malignancies

R306465 is a novel potent inhibitor of class I histone deacetylases with broad-spectrum antitumoral activity against solid and haematological malignancies

Depression of mitochondrial metabolism by downregulation of cytoplasmic deacetylase, HDAC6

Histone Deacetylase Inhibitors: A Brief Overview Of Their Role And Medicinal Chemistry

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