HDAC6 promotes cell proliferation and confers resistance to temozolomide in glioblastoma

Wang, Zhihao; Hu, Pengchao; Tang, Fang; Lian, Haiwei; Xiong, Chen; Zhang, Yingying; He, Xiaohua; Liu, Wanhong; Xie, Conghua

doi:10.1016/j.canlet.2016.06.001

Cited by 78 publications

(70 citation statements)

References 48 publications

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“…50 Nonetheless, promising results have been obtained combining selective HDAC6i at low concentrations with Temozolomide, an alkylating agent used for the treatment of glioblastoma multiforme, or with Cisplatin in non-small cell lung cancer cells. 27,[51][52][53] One of the most studied combinatory therapies concerning HDAC6i, is their use with proteasome inhibitors, such as Bortezomib and Carfilzomib, for the treatment of multiple myeloma. In most cases Ricolinostat was used, but with concentrations ranging from 1 to 4 μM, this approach is likely to result in off-target effects on other HDACs.…”

Section: Discussionmentioning

confidence: 99%

Selective pharmacological inhibitors of HDAC6 reveal biochemical activity but functional tolerance in cancer models

Depetter

Geurs

Vreese

et al. 2019

Intl Journal of Cancer

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Our study investigates the biochemical and functional impact of selective histone deacetylase 6 (HDAC6) inhibitors, a promising class of novel therapeutics, in several cancer models. Selective HDAC6 inhibitors (Tubathian A, Tubastatin A, Tubacin and Ricolinostat) and a non‐selective HDAC inhibitor (Vorinostat) were evaluated on cancer cell lines derived from multiple tumour types in both an in vitro and in vivo setting as potential cancer therapeutics. Selective HDAC6 inhibitors resulted in α‐tubulin acetylation with no impact on histone acetylation but failed to show any anti‐cancer properties. Only the use of high concentrations of selective HDAC6 inhibitors resulted in co‐inhibition of other HDAC enzymes and consequently in reduced growth, migratory and/or invasive activity of cancer cells in vitro as well as in vivo. The specificity of HDAC6 inhibition was confirmed using a CRISPR/Cas9 knockout cell line. Our results suggest that selective HDAC6 inhibitors may fall short as potential single agent anti‐cancer drugs and prove that many previous data regarding this promising class of compounds need to be interpreted with great care due to their use in high concentrations resulting in low selectivity and potential off‐target effects.

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Section: Discussionmentioning

confidence: 99%

Selective pharmacological inhibitors of HDAC6 reveal biochemical activity but functional tolerance in cancer models

Depetter

Geurs

Vreese

et al. 2019

Intl Journal of Cancer

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“…These findings indicate HDAC6 as a potential therapeutic target for cancer therapy [76]. Aberrant expression patterns of HDAC6 are found in various cancers, including breast cancer [77], oral squamous cell carcinoma [78], ovarian cancer [79], GBM [80], and mouse tumor models. Recently, Wang et al reported that HDAC6 increases proliferation and imparts temozolomide resistance in GBM [80].…”

Section: Preclinical Studies Of Hdacs and Hdac Inhibitors In Gbmmentioning

confidence: 99%

Advances in epigenetic glioblastoma therapy

et al. 2017

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Glioblastoma multiforme (GBM) is the most lethal primary brain tumor in adults despite contemporary gold-standard first-line treatment strategies. This type of tumor recurs in virtually all patients and no commonly accepted standard treatment exists for the recurrent disease. Therefore, advances in all scientific and clinical aspects of GBM are urgently needed. Epigenetic mechanisms are one of the major factors contributing to the pathogenesis of cancers, including glioblastoma. Epigenetic modulators that regulate gene expression by altering the epigenome and non-histone proteins are being exploited as therapeutic drug targets. Over the last decade, numerous preclinical and clinical studies on histone deacetylase (HDAC) inhibitors have shown promising results in various cancers. This article provides an overview of the anticancer mechanisms of HDAC inhibitors and the role of HDAC isoforms in GBM. We also summarize current knowledge on HDAC inhibitors on the basis of preclinical studies and emerging clinical data.

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“…Contrary to nuclear HDACs implicated in epigenetic regulation of transcription, HDAC6 is a mainly localized cytoplasmic deacetylase involved in “non-histone” functions 18 . HDAC6 is overexpressed in many cancers and HDAC6 inhibitors display beneficial effects in various experimental models of cancer that shares several features with PAH 19, 20 . Importantly, HDAC6 does not deacetylate histones, and accordingly, the anticancer effects of the HDAC6-specific inhibitors are not associated with disrupted epigenetic control of gene transcription 21 .…”

Section: Introductionmentioning

confidence: 99%

HDAC6: A Novel Histone Deacetylase Implicated in Pulmonary Arterial Hypertension

Boucherat

Chabot

Paulin

et al. 2017

Sci Rep

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Pulmonary arterial hypertension (PAH) is a vascular remodeling disease with limited therapeutic options. Although exposed to stressful conditions, pulmonary artery (PA) smooth muscle cells (PASMCs) exhibit a “cancer-like” pro-proliferative and anti-apoptotic phenotype. HDAC6 is a cytoplasmic histone deacetylase regulating multiple pro-survival mechanisms and overexpressed in response to stress in cancer cells. Due to the similarities between cancer and PAH, we hypothesized that HDAC6 expression is increased in PAH-PASMCs to face stress allowing them to survive and proliferate, thus contributing to vascular remodeling in PAH. We found that HDAC6 is significantly up-regulated in lungs, distal PAs, and isolated PASMCs from PAH patients and animal models. Inhibition of HDAC6 reduced PAH-PASMC proliferation and resistance to apoptosis in vitro sparing control cells. Mechanistically, we demonstrated that HDAC6 maintains Ku70 in a hypoacetylated state, blocking the translocation of Bax to mitochondria and preventing apoptosis. In vivo, pharmacological inhibition of HDAC6 improved established PAH in two experimental models and can be safely given in combination with currently approved PAH therapies. Moreover, Hdac6 deficient mice were partially protected against chronic hypoxia-induced pulmonary hypertension. Our study shows for the first time that HDAC6 is implicated in PAH development and represents a new promising target to improve PAH.

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HDAC6 promotes cell proliferation and confers resistance to temozolomide in glioblastoma

Cited by 78 publications

References 48 publications

Selective pharmacological inhibitors of HDAC6 reveal biochemical activity but functional tolerance in cancer models

Selective pharmacological inhibitors of HDAC6 reveal biochemical activity but functional tolerance in cancer models

Advances in epigenetic glioblastoma therapy

HDAC6: A Novel Histone Deacetylase Implicated in Pulmonary Arterial Hypertension

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