15-Deoxy-△12,14-prostaglandin J2 upregulates the expression of 15-hydroxyprostaglandin dehydrogenase through DNA methyltransferase 1 inactivation

Abstract

15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is the key enzyme that catalyzes the degradation of prostaglandin E2. The expression of 15-PGDH is ubiquitously down-regulated in various cancers, and hence considered as a tumor suppressor. Hypermethylation of CpG islands in the gene promoter region is an important mechanism to silence the expression of tumor suppressor genes and contributes to cancer formation. 15-Deoxy-△12,14-prostaglandin J2 (15d-PGJ2), one of the terminal products of cyclooxygenase-2, has been reported to have anti-inflammatory and anti-carcinogenic activities. The aim of this study is to investigate the effect of 15d-PGJ2 on DNA methylation. In the present study, we demonstrated that 15d-PGJ2 up-regulated 15-PGDH expression by decreasing the level of CpG methylation in 15-PGDH promoter regions in human breast cancer MDA-MB-231 cells. 15d-PGJ2 inhibited the activity of DNA methyltransferase 1 (DNMT1) which is the major enzyme responsible for maintaining DNA methylation. However, 15d-PGJ2 showed no effects on expression of either mRNA or protein of DNMT1. We notably found that 15d-PGJ2 directly interacted with DNMT1, thereby reducing its catalytic activity. However, a non-electrophilic analogue 9,10-dihydro-15d-PGJ2 failed to suppress the methylation of CpG islands present in 15-PGDH promoter, suggesting that the α,β-unsaturated carbonyl group is essential for 15d-PGJ2-mediated inactivation of DNMT1 and subsequent up-regulation of 15-PGDH expression. Chromatin-immunoprecipitation (ChIP) analysis revealed that 15d-PGJ2 significantly attenuated DNMT1 binding to the 15-PGDH promoter regions. Taken together, these findings suggest that 15d-PGJ2 increases 15-PGDH expression by suppressing DNMT1-mediated hypermethylation of 15-PGDH promoter.