m6A-modified PADI2 facilitates proliferation and Cisplatin-resistance of epithelial ovarian cancer

Objective: Chemotherapy resistance remains a barrier to improving the prognosis of epithelial ovarian cancer (EOC), and among several novel approaches to overcome chemotherapy resistance, modulating N6- methyladenosine (m6A) RNA modification was found to be an important strategy. However, the mechanism of m6A regulator genes in EOC chemotherapy resistance has not been fully elucidated. Methods: We found out the target genes through bioinformatics and verified them through cell biology experiments, animal experiments, etc. Results: Here, we found that Peptidyl Arginine Deiminase 2 (PADI2) was upregulated and highly m6A methylated in EOC samples and correlated with poor outcome. PADI2 downregulation suppressed colony formation, cell proliferation and cisplatin (cDDP) resistance in EOC cells. Furthermore, we identified METTL3 as the m6A writer of PADI2 mRNA, YTHDF2 recognizes and binds m6A-methylated PADI2 mRNA, which augments the translation of PADI2, thus activating the JAK2/STAT3 pathway and facilitating cDDP resistance in EOC cells in vitro and vivo. In addition, METTL3 or YTHDF2 knockdown decreased the expression of PADI2 mRNA and suppressed tumor growth and cDDP resistance. Conclusion: Collectively, we identified a novel mechanism underlying the induction of cDDP resistance and EOC progression by m6A-modified PADI2, which can serve as a target to develop therapeutics for EOC treatment.