Rationale:
Prostaglandin E2 (
PGE2) is a pro-inflammatory
eicosanoid up-regulated in
gastric cancer (GC). However, its impact on epigenetic dysfunction in the process of gastric
carcinogenesis is unknown. In this study, we investigate the role of
PGE2 in DNA methylation in gastric epithelium in vitro, in mice, and humans. Methods: PGE2-induced DNMT3B and DNA methylation was determined in gastric cell lines and COX-2 transgenic mice. Effect of COX-2 inhibition on DNA methylation was evaluated in a randomized controlled trial. Efficacy of combined COX-2/
PGE2 and DNMT inhibition on GC growth was examined in cell lines and mice models. Results: PCR array analysis of PGE2-treated GC cells revealed the up-regulation of DNMT3B, a de novo
DNA methyltransferase. In GC cells,
PGE2 induced DNMT3B expression and activity, leading to increased methylated
cytosine (5mC) and promoter methylation of
tumor suppressive genes (MGMT and CNR1). Consistently, Cox-2 (rate-limiting
enzyme for
PGE2 biosynthesis) transgenic expression in mice significantly induced Dnmt3b expression, increased 5mC content, and promoted Mgmt promoter methylation. We retrospectively analyzed the 5mC content of 42 patients with intestinal
metaplasia (a precancerous lesion of GC) treated with a COX-2 specific inhibitor
Rofecoxib or placebo for 2 years, revealing that the
COX-2 inhibitor significantly down-regulated 5mC levels (N=42, P=0.009). Collectively, these data indicate that
PGE2 is closely related to
DNA hypermethylation in vitro and in vivo. Using genome-wide 450K methylation array, we identified chromosomal genes (POT1, ATM and HIST1H2AA) were preferentially methylated by
PGE2. Biofunctional work revealed that POT1 functions as a
tumor suppressor. Finally, we demonstrated that combinatorial inhibition of COX-2 and DNMT using
Celecoxib and
Decitabine synergistically inhibited GC growth in vitro and in vivo. Conclusion: This study suggested that
PGE2 promotes DNA methylation in GC, and that co-targeting of
PGE2 and DNMT inhibits GC.