N6-methyladenosine modification of MRP7 mRNA modulates its expression and paclitaxel sensitivity in lung cancer-derived A549 cells.

Methylation of adenosine at the N6 position (m6A modification) is the most prevalent epitranscriptomic modification in mammals, regulating RNA stability, splicing, translation, and decay. Growing evidence has revealed that m6A modification is intricately linked to cancer progression. This study aimed to investigate the effects of m6A modification on the sensitivity of lung cancer-derived A549 cells to paclitaxel (PTX). Knockdown of methyltransferase like (METTL) 3/14, the m6A writer complex, increased A549 cell viability under PTX, indicating m6A modification enhances PTX sensitivity. METTL3/14 knockdown increased the expression of multidrug resistance-associated protein (MRP) 7, but not multiple drug resistance (MDR) 1 or MRP1, promoting PTX efflux. RNA immunoprecipitation showed that MRP7 mRNA is highly methylated at the 5'-untranslated region (UTR), coding region, and 3'-UTR. METTL3/14 knockdown stabilized MRP7 mRNA, while depletion of m6A readers YTHDC2 or YTHDF2 also elevated MRP7 mRNA, suggesting these readers mediate its degradation. Moreover, knockdown of the erasers fat mass and obesity-associated protein (FTO) or AlkB homolog 5 as well as treatment with entacapone, an FTO inhibitor, increased PTX sensitivity in PTX-resistant A549 cells. These results suggest that the m6A-dependent regulation of MRP7 expression contributes to PTX resistance, highlighting a potential therapeutic avenue in lung cancer.