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Theranostics 2019; 9(21):6256-6268. doi:10.7150/thno.35766 This issue Cite

Research Paper

Prostaglandin E₂ induces DNA hypermethylation in gastric cancer in vitro and in vivo

Chi Chun Wong^1✉, Wei Kang², Jiaying Xu¹, Yun Qian^1,3, Simson Tsz Yat Luk¹, Huarong Chen¹, Weilin Li^1,4, Liuyang Zhao¹, Xiaoming Zhang¹, Phlip WY Chiu², Enders KW Ng², Jun Yu^1✉

1. Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong.
2. Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong
3. Department of Gastroenterology, Shenzhen University General Hospital, Shenzhen University Clinical Medical Academy, Shenzhen, China
4. Department of Surgery, The Chinese University of Hong Kong, Hong Kong

✉ Corresponding authors: Dr. Chi Chun Wong and Professor Jun Yu, Department of Medicine and Therapeutics, Prince of Wales Hospital, the Chinese University of Hong Kong, Shatin, NT, Hong Kong. Tel: (852) 37636108; Fax: (852) 21445330; Email: chichun.wongedu.hk; junyuedu.hk More

Abstract

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.

Keywords: Gastric cancer, COX-2 transgenic mice, Prostaglandin E₂, DNA methylation, DNMT3B

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