N 6-methyladenosine promotes temozolomide resistance through mRNA stabilization in glioblastoma cells.

چکیده اصلی

N 6-methyladenosine (m6A) regulates nearly every aspect of messenger RNA (mRNA) processing and function, impacting downstream gene expression programs. Changes in m6A have been implicated in many different types of cancer, and inhibition of m6A installation is emerging as a cancer therapeutic strategy. However, chemoresistance remains a significant clinical challenge in the treatment of glioblastoma (GBM). We established GBM cell culture models of acquired temozolomide (TMZ) resistance, analyzed the role of m6A in controlling resistance-associated pathways, and assessed the effects of METTL3 inhibition. We show that m6A stabilizes key genes and pathways promoting TMZ resistance, and that METTL3 inhibition can reverse this and restore TMZ sensitivity. These findings highlight that TMZ resistance can occur independent of a glioma stem cell population and that changes in m6A need not be driven by changes in METTL3 expression. Collectively, our results suggest that genes associated with TMZ resistance are stabilized by m6A methylation even as the majority of the transcriptome remains subject to m6A-mediated mRNA decay. Moreover, these data highlight METTL3 inhibition as a promising therapeutic approach to overcoming TMZ resistance in GBM.

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