Abstract 4452: Oxdative stress suppresses the expression of 15-hydroxyprostaglandin dehydrogenase via upregulation of DNMT3a/Snail in human colon epithelial cells Free

Overproduction of prostaglandin E2 (PGE2) is implicated in pathogenesis of inflammation-associated carcinogenesis. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is a key enzyme that catalyzes the conversion of PGE2 to biologically inactive 15-keto-PGE2 metabolite. 15-PGDH has been considered to be a tumor suppressor as its expression is frequently repressed in human malignancies via hypermethylation of its promoter. In our previous study, oxidative stress caused by Helicobacter pylori infection suppressed the expression of 15-PGDH. Reactive oxygen species (ROS) can induce methylation as well as mutation of genes including those that encode tumor suppressor proteins, thereby contributing to carcinogenesis. This prompted us to investigate whether 15-PGDH expression could be down-regulated by oxidative stress in normal colon epithelial CCD841 cells. When CCD841 cells were treated with H2O2, the expression level of 15-PGDH was significantly reduced in both concentration and time dependent manners. Hydrogen peroxide (300 μM) induced the expression of DNA methyltransferase (DNMT) 3a, which was blocked by an inhibitor of DNMT, 5-Aza-2′-deoxycytidine (5-Aza). The 5-Aza abrogated the down-regulation of 15-PGDH expression induced by H2O2. The antioxidant, N-acetylcysteine (NAC) abrogated the down-regulation of 15-PGDH and upregulation of DNMT 3a expression induced by H2O2. The transcriptional repressor Snail plays a central role in the suppression of 15-PGDH expression. H2O2 treatment also elevated expression of Snail, which was abrogated by NAC and 5-Aza. Taken together, these finding suggest that ROS suppresses the expression of 15-PGDH through hypermethylation of CpG island in the 15-PGDH promoter.

Citation Format: Ja-Young Lee, Jeong-Eun Lee, Hye Kyung Na. Oxdative stress suppresses the expression of 15-hydroxyprostaglandin dehydrogenase via upregulation of DNMT3a/Snail in human colon epithelial cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4452.