Regulation of temozolomide resistance by m6A mRNA methylation in glioma cell lines

N6-methyladenosine (m6A) is a critical regulator of mRNA processing and function, playing roles in mRNA processing, translation, and decay. Changes in m6A status have been implicated in various cancers, including glioblastoma (GBM), where acquired chemoresistance to temozolomide (TMZ) remains a major clinical challenge. We developed cell culture models of acquired TMZ resistance in GBM and analyzed the regulation of resistance-associated genes and pathways by m6A. We find that key resistance-associated genes and pathways are regulated by m6A methylation, including MGMT, the enzyme that repairs primary TMZ-induced DNA damage. Inhibition of METTL3 with STM2457 treatment destabilizes MGMT mRNA. Intriguingly, other TMZ resistance-associated genes are similarly regulated by m6A, suggesting that METTL3 inhibition may represent a promising therapeutic approach for overcoming TMZ resistance.