In vivo destabilization of dynamic microtubules by HDAC6-mediated deacetylation

Matsuyama, Akihisa; Shimazu, Tadahiro; Sumida, Yuko; Saito, Akiko; Yoshimatsu, Yasuhiro; Seigneurin-Berny, Daphné; Osada, Hiroyuki; Komatsu, Yasuhiko; Nishino, Norikazu; Khochbin, Saadi; Horinouchi, Sueharu; Yoshida, Minoru

doi:10.1093/emboj/cdf682

Cited by 629 publications

(584 citation statements)

References 43 publications

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“…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%

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: Resultsmentioning

confidence: 99%

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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“…4a,b). Physiologically, acetylation of tubulin occurs preferentially on polymerized MT 33 , whereas deacetylation of a-tubulin by HDAC6 is thought to occur when a-tubulin is in a heterodimeric state 34 . Therefore, HDAC6 might be a target of Ab, translating its effect on tubulin acetylation.…”

Section: Ab Increases Mt Dynamics and Increases Acetylated Tubulinmentioning

confidence: 99%

HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity

et al. 2015

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Maintenance of neuronal polarity and regulation of cytoskeletal dynamics are vital during development and to uphold synaptic activity in neuronal networks. Here we show that soluble b-amyloid (Ab) disrupts actin and microtubule (MT) dynamics via activation of RhoA and inhibition of histone deacetylase 6 (HDAC6) in cultured hippocampal neurons. The contact of Ab with the extracellular membrane promotes RhoA activation, leading to growth cone collapse and neurite retraction, which might be responsible for hampered neuronal pathfinding and migration in Alzheimer's disease (AD). The inhibition of HDAC6 by Ab increases the level of heterodimeric acetylated tubulin and acetylated tau, both of which have been found altered in AD. We also find that the loss of HDAC6 activity perturbs the integrity of axon initial segment (AIS), resulting in mislocalization of ankyrin G and increased MT instability in the AIS concomitant with loss of polarized localization of tau and impairment of action potential firing.

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“…Cytoplasmic HDAC6 shows striking co-localization with the microtubule network [87,88]. Acetylation of a-tubulin, at lysine 40, has been used as a marker of microtubule stability [89].…”

Section: Tigs 54mentioning

confidence: 99%

“…Acetylation of a-tubulin, at lysine 40, has been used as a marker of microtubule stability [89]. HDAC6 functions as a specific tubulin deacetylase in vivo, and purified HDAC6 deacetylates a-tubulin in assembled microtubules in vitro [87,88]. HDAC6 overexpression promotes chemotactic cell movement, a cellular function dependent on microtubules.…”

Section: Tigs 54mentioning

confidence: 99%

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Class II histone deacetylases: versatile regulators

2003

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Histone acetylation and deacetylation play essential roles in modifying chromatin structure and regulating gene expression in eukaryotes. Histone deacetylases (HDACs) catalyze the deacetylation of lysine residues in the histone N-terminal tails and are found in large multiprotein complexes with transcriptional co-repressors. Human HDACs are grouped into three classes based on their similarity to known yeast factors: class I HDACs are similar to the yeast transcriptional repressor yRPD3, class II HDACs to yHDA1 and class III HDACs to ySIR2. In this review, we focus on the biology of class II HDACs. These newly discovered enzymes have been implicated as global regulators of gene expression during cell differentiation and development. We discuss their emerging biological functions and the molecular mechanisms by which they are regulated.

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In vivo destabilization of dynamic microtubules by HDAC6-mediated deacetylation

Cited by 629 publications

References 43 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

HDAC6 and RhoA are novel players in Abeta-driven disruption of neuronal polarity

Class II histone deacetylases: versatile regulators

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