RNA modification control of platinum sensitivity via ADAM23-dependent pathway

N6-methyladenosine (m6A) is the most common modification involved in post-transcriptional regulation of RNA, affecting stability, splicing, and translation. M⁶A modifications are regulated by methyltransferases (“writers”) and demethylases (“erasers”). Methyltransferase-like 3 (METTL3) is one of the m⁶A writer complexes, catalyzing the m6A modification by transferring a methyl group to the N6 position of adenosine. METTL3 has been implicated in tumor development by modulating m⁶A distribution and promoting the translation of oncogenic transcripts. Overcoming platinum resistance in ovarian cancer is a significant clinical challenge; therefore, we hypothesized that METTL3-mediated m⁶A methylation contributes to resistance by altering cellular response to platinum drugs. We assessed m⁶A and METTL3 expression after cisplatin treatment using RT-qPCR and western blotting. To evaluate their functional role, we measured the IC₅₀ of cisplatin in ovarian cancer cell lines with METTL3 overexpression or knockdown. Additionally, the METTL3 inhibitor STM2457 was utilized to investigate the role of METTL3 in ovarian cancer, both in vitro and in vivo. Cisplatin treatment upregulated m⁶A and METTL3 levels. METTL3 overexpression enhanced platinum resistance. Conversely, METTL3 knockdown or STM2457 treatment sensitized cells to cisplatin. RNA-seq analysis identified ADAM23 as a downstream target of METTL3. ADAM23 is a member of the ADAM (a disintegrin and metalloprotease) family involved in cell adhesion and extracellular matrix interactions. The protease is silenced in various tumors, including breast, gastric, pancreatic cancers, and gliomas. In ovarian cancer cell lines, ADAM23 expression was inversely correlated with METTL3 levels, showing decreased expression upon METTL3 overexpression and increased expression following METTL3 knockdown. Notably, cisplatin treatment led to reduced ADAM23 expression through METTL3 upregulation. Further analysis using SRAMP identified several very high confidence m6A modification sites on ADAM23 mRNA in human. These findings suggest that METTL3-mediated m⁶A modifications, through regulation of ADAM23, may represent a novel therapeutic target in ovarian cancer.