Abstract 4074: Prostaglandin E2 promotes intestinal tumor growth via DNA methylation

Abstract

Abstract Both chronic inflammation and DNA methylation have been implicated as early events during colorectal cancer (CRC) carcinogenesis. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk for colorectal cancer (CRC) by 40-50%. NSAIDs exert some of their anti-inflammatory or anti-tumor effects by inhibiting prostaglandin-endoperoxide synthase (PTGS) 1 and 2. PTGS2-derived prostaglandin E2 (PGE2) is a pro-inflammatory mediator and promotes tumor progression. Promoter DNA methylation may promote tumor growth through silencing tumor suppressor or DNA repair genes. Whether chronic inflammation, specifically in this study the pro-inflammatory factor PGE2, plays a role in DNA methylation and contributes to CRC carcinogenesis is unknown. Here we demonstrated that PGE2 upregulated DNA methyltransferase (DNMT) 1 and 3B, which resulted to increased DNA methylation in the promoters of target genes O6-methylguanine-DNA methyltransferase (MGMT), cannabinoid receptor 1 (CNR1), CDKN2B, and MutL homolog 1 (MLH1) in CRC cell lines. Meanwhile, the expression of MGMT, CNR1, CDKN2B, and MLH1 were decreased. EP4 antagonist blocked the upregulation of DNMT1 and DNMT3B while knockdown of DNMT1 or DNMT3B attenuated the dwonregulation of MGMT, CNR1, CDKN2B, and MLH1 by PGE2 in LS-174T cells. In ApcMin/+ mice, PGE2 treatment also increased the expression of DNMT1 and DNMT3B and the DNA methylation of MGMT, CNR1, CDKN2B, and MLH1 promoters, and reduced their expression. All these alterations were accompanied by increases in both polyp number and size in the intestines of ApcMin/+ mice. More intriguingly, a demethylating agent 5-Aza-dC blocked the PGE2-induced DNA methylation and tumor growth in ApcMin/+ mice. And a combination treatment with a selective PTGS2 inhibitor celecoxib and 5-Aza-dC more effectively reduced the polyp number and size in ApcMin/+ mice in comparison with either single agent. Furthermore, the levels of PTGS2 and PGE2 correlated with the expression of DNMT1 and DNMT3B; The DNA methylation of MGMT, CNR1, and MLH1 correlated with the levels of PTGS2, PGE2, DNMT1, and DNMT3B in human colorectal carcinomas. These results suggest that PGE2 can silence tumor suppressor or DNA repair genes via DNA methylation to promote CRC carcinogenesis. 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 4074. doi:1538-7445.AM2012-4074