Sinomenine increases the methylation level at specific GCG site in mPGES-1 promoter to facilitate its specific inhibitory effect on mPGES-1

Abstract

Prostaglandin E₂ (PGE₂) in cancer and inflammatory diseases is a key mediator of disease progression. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to inhibit the expression of PGE₂ by depressing cyclooxygenase (COX) in inflammatory treatments. However, the inhibition to COXs may cause serious side effects. Thus, it is urgent to develop new anti-inflammatory drugs aiming new targets to inhibit PGE₂ production. Microsomal prostaglandin E synthase 1 (mPGES-1) catalyzes the final step of PGE₂ biosynthesis. Therefore, the selective inhibition of mPGES-1 has become a promising strategy in the treatments of cancer and inflammatory diseases. Our previous studies confirmed that sinomenine (SIN) is a specific mPGES-1 inhibitor. However, the exact mechanism by which SIN inhibits mPGES-1 remains unknown. This study aimed to explain the regulation effect of SIN to mPGES-1 gene expression by its DNA methylation induction effect. We found that the demethylating agent 5-azacytidine (5-AzaC) reversed the inhibitory effect of SIN to mPGES-1. Besides, SIN selectively increased the methylation level of the promoter region in the mPGES-1 gene while the pretreatment of 5-AzaC suppressed this effect. The results also shows that pretreatment with SIN increased the methylation level of specific GCG sites in the promoter region of mPGES-1. This specific methylation site may become a new biomarker for predicting and diagnosing RA and cancer with high expression of mPGES-1. Also, our research provides new ideas and solutions for clinical diagnosis and treatment of diseases related to mPGES-1 and for targeted methylation strategy in drug development.

Keywords: Anti-inflammation; DNA methylation; Microsomal prostaglandin E synthase 1; Promoter; Sinomenine.