This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gillenwater, A. M. Articles by Lotan, R. Search for Related Content PubMed PubMed Citation Articles by Gillenwater, A. M. Articles by Lotan, R.

Research Articles: Therapeutics, Targets, and Development

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

Departments of ¹ Head and Neck Surgery and ² Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Ann M. Gillenwater, Department of Head and Neck Surgery, Unit 441, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-8841; Fax: 713-794-4662. E-mail: agillenw{at}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. [Mol Cancer Ther 2007;6(11):2967–75]

Grant support: Department of Defense grant DAMD17-02-1-0706, NIH grant P50 CA97007-01, and Specialized Programs of Research Excellence in Head and Neck Cancer and Cancer Center Support grant P30 CA16672.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 12/21/04; revised 9/13/07; accepted 9/25/07.

This article has been cited by other articles:

				G. Zhang, M. A. Park, C. Mitchell, H. Hamed, M. Rahmani, A. P. Martin, D. T. Curiel, A. Yacoub, M. Graf, R. Lee, et al. Vorinostat and Sorafenib Synergistically Kill Tumor Cells via FLIP Suppression and CD95 Activation Clin. Cancer Res., September 1, 2008; 14(17): 5385 - 5399. [Abstract] [Full Text] [PDF]