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Mol Cancer Ther. 2007 Nov;6(11):2967-75.

Histone deacetylase inhibitor suberoylanilide hydroxamic acid induces apoptosis through both mitochondrial and Fas (Cd95) signaling in head and neck squamous carcinoma cells.

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1
Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. agillenw@mdanderson.org

Abstract

Alterations in histone acetylation status have been implicated in carcinogenesis. Histone deacetylase inhibitors, such as suberoylanilide hydroxamic acid (SAHA), can potentially reactivate aberrantly silenced genes by restoring histone acetylation and allowing gene transcription. However, the mechanisms underlying the effects of SAHA on cell growth, differentiation, and death remain unclear. In this study, we assessed the activity of SAHA in modulating cell growth and apoptosis in head and neck squamous cell carcinoma (HNSCC) cells compared with premalignant leukoplakia and normal oral cells. SAHA induced growth inhibition, cell cycle changes, and apoptosis in HNSCC cell lines but had limited effects on premalignant and normal cells. Although SAHA triggered the mitochondrial pathway of apoptosis, including cytochrome c release, caspase-3 and caspase-9 activation, and poly(ADP-ribose) polymerase cleavage in HNSCC cells, specific inhibition of caspase-9 only partially blocked the induction of apoptosis induction. SAHA also activated the extrinsic apoptosis pathway, including increased Fas and Fas ligand (FasL) expression, activation of caspase-8, and cleavage of Bid. Interfering with Fas signaling blocked apoptosis induction and blunted growth inhibition by SAHA. Our results show for the first time that SAHA induces apoptosis in HNSCC cells through activation of the Fas/FasL death pathway in addition to the intrinsic mitochondrial pathway although having comparatively little activity against precancerous and normal oral cells with intrinsic Fas and FasL expression.

PMID:
18025281
DOI:
10.1158/1535-7163.MCT-04-0344
[Indexed for MEDLINE]
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