METTL3-mediated m ⁶ A modification of DNMT1 enhances ovarian cancer progression

High-grade serous ovarian carcinoma (HGSOC), the most lethal subtype of ovarian cancer, is often diagnosed at advanced stages and remains associated with poor clinical outcome. In this study, we identify a critical oncogenic role of the RNA methyltransferase METTL3 and the N ⁶ -methyladenosine (m ⁶ A) RNA modification pathway in HGSOC. Suppression of METTL3, either genetically or pharmacologically, and depletion of its binding partner METTL14 impair ovarian cancer proliferation and tumor progression. Mechanistically, we show that METTL3-mediated m ⁶ A deposition enhances the translation of DNA methyltransferase 1 (DNMT1), the primary maintenance DNA methyltransferase responsible for preserving genome-wide methylation patterns and silencing tumor suppressor genes. Pharmacological inhibition of DNMT1 induces widespread DNA hypomethylation and up-regulation of the tumor suppressors TNFAIP3 and FBXO32. Consistently, METTL3 suppression reduces DNMT1 abundance and derepresses TNFAIP3 and FBXO32 expression. Knockdown and rescue studies further reveal that DNMT1 primarily mediates METTL3-dependent regulation of cell migration, whereas the antiproliferative effects of METTL3 suppression are likely driven by additional downstream targets. Collectively, these findings identify the m ⁶ A-METTL3-DNMT1 axis as a mechanistic link between RNA and DNA methylation pathways and a potential therapeutic vulnerability in HGSOC.