m6A-mediated regulation of CPSF6 by METTL3 promotes oxaliplatin resistance in colorectal cancer through enhanced glycolysis.

Oxaliplatin resistance poses a significant challenge in colorectal cancer (CRC) treatment. Recent studies have implicated CPSF6 in cancer progression and drug resistance, although its role in chemotherapy resistance and regulatory mechanisms is unclear. This study investigates CPSF6's involvement in oxaliplatin resistance in CRC and its regulation via m6A methylation by METTL3. We assessed CPSF6 expression in oxaliplatin-resistant (OxR) CRC cell lines (HT29-OxR and HCT116-OxR) compared to sensitive counterparts using qRT-PCR and Western blotting. CPSF6 was significantly upregulated in OxR cells, and its knockdown reduced cell viability, colony formation, and glycolytic activity while increasing apoptosis. m6A modification of CPSF6 mRNA was elevated in OxR cells, correlating with increased METTL3 expression. METTL3 knockdown decreased CPSF6 levels and m6A enrichment, enhancing mRNA degradation, while its overexpression stabilized CPSF6 mRNA, promoting resistance. Xenograft experiments showed that CPSF6 knockdown suppressed tumor growth and glycolysis. Thus, CPSF6 is identified as a mediator of oxaliplatin resistance in CRC, regulated by the METTL3/m6A axis, suggesting potential therapeutic targets to overcome resistance.