Abstract 5352: Dysregulation of the repressive H3K27 trimethylation mark in head and neck squamous cell carcinoma contributes to dysregulated squamous differentiation.

Abstract

Abstract Head and neck squamous cell carcinoma (HNSCC) is one of the most prevalent cancers diagnosed worldwide and is associated with a 5-year survival rate of 55%. EZH2, a component of the polycomb repressor complex 2, trimethylates H3K27 (H3K27me3); which has been shown to drive squamous differentiation in normal keratinocytes. This study determined whether inhibition of EZH2-mediated epigenetic silencing could induce differentiation or provide therapeutic benefit in HNSCC. We determined the effects of inhibiting EZH2, by either RNA interference or pharmacologically, on HNSCC growth, viability and differentiation in vitro. Xenografts of HNSCC cell lines were used to assess efficacy of 3-Deazaneplanocin A (DZNep), an inhibitor of H3K27 trimethylation, in vivo. EZH2 was highly expressed in HNSCC cell lines in vitro and tissue microarray analysis revealed high expression in (n= 59) in situ relative to normal oral epithelium (n=12). Inhibition of EZH2 with siRNA could induce expression of differentiation genes in differentiation-refractory squamous cell carcinoma cell lines. Differentiation-refractory HNSCC cell lines displayed persistent H3K27me3 on the promoters of differentiation genes. DZNep caused cancer-cell specific apoptosis in addition to a profound reduction in colony forming efficiency and induction of some squamous differentiation genes. Furthermore, in vivo, DZNep attenuated tumour growth in two different xenograft models, caused intra-tumour inhibition of EZH2 and induction of differentiation genes in situ. Collectively, these data suggest that aberrant differentiation in HNSCC may be attributed to epigenetic dysregulation and suggests that inhibition of PRC2-mediated gene repression may represent a potential therapeutic target. Citation Format: Orla M. Gannon, Lilia Merida de Long, Liliana Endo Munoz, Mehlika Hazar Rethinam, Nicholas Saunders. Dysregulation of the repressive H3K27 trimethylation mark in head and neck squamous cell carcinoma contributes to dysregulated squamous differentiation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5352. doi:10.1158/1538-7445.AM2013-5352