Epithelial to mesenchymal transition is a developmental pathway that has been shown to have a direct role in tumor progression and drug resistance. Increasing evidence suggests that EMT (and MET) leads to global changes in chromatin architecture that modifies expression of numerous genes. Interestingly, reports in the literature indicate a possible association between cyclooxygenase-2 (COX-2) expression and EMT. COX-2 is upregulated in response to inflammation, and is known to be overexpressed in multiple malignancies, including pancreatic cancer. As a critical mediator of prostaglandin production, COX-2 has proangiogenic properties associated with increased tumor growth and invasion, and is also thought to play a role in the carcinogenic process. In this study, we report that COX-2 expression is associated with an epithelial phenotype among a panel of human pancreatic cancer cells. Using chromatin immunoprecipitation (ChIP), we demonstrate increased acetylated H3 at the COX-2 promoter region in the epithelial cell lines versus mesenchymal cell lines. Treatment with a Type-I selective HDAC inhibitor SNDX-275 increased levels of acetylation at the COX-2 promoter region in mesenchymal cell lines and subsequently promoted COX-2 gene expression. Overall, these data point to an epigenetic suppression of COX-2 expression in mesenchymal pancreatic cancer cells that can be reversed by Type-I HDAC inhibitors. Our results suggest that COX2 inhibitors will preferentially target “epithelial” pancreatic cancers and that combinations of Cox2 and HDAC inhibitors may display increased anti-tumor activity.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4098. doi:1538-7445.AM2012-4098