MAPK13 stabilization via m⁶A modification limits anti-cancer efficacy of rapamycin

Abstract

N6-adenosine methylation (m6A) is the most abundant mRNA modification that controls gene expression through multiple diverse mechanisms. m6A-dependent regulation of oncogenes and tumor suppressors indeed contribute to tumor development. However, the role of m6A-mediated gene regulation after drug treatment or resistance is poorly understood. Here, we report that m6A modification of mitogen-activated protein kinase 13 (MAPK13) determines the sensitivity of cancer cells to the mechanistic target of rapamycin complex 1 (mTORC1) 1-targeting chemotherapeutic agent rapamycin. mTORC1 induces m6A modification of MAPK13 mRNA at its 3′ untranslated region (3′UTR) through methyltransferase-like 3 (METTL3)-METTL14-Wilms' tumor 1-associating protein (WTAP) methyltransferase complex, thereby stimulating its mRNA degradation via an m6A reader protein YTH domain family proteins 2 (YTHDF2). Rapamycin blunts this process and stabilizes MAPK13. Unexpectedly, MAPK13 silencing suppresses cell growth and enhances rapamycin′s anti-cancer effects, suggesting that MAPK13 is an oncogenic gene activated by rapamycin through negative feedback regulation. Together, our data indicate that rapamycin-mediated MAPK13 mRNA stabilization may confer drug resistance, and it can thus be a therapeutic target to sensitize cancer cells to rapamycin.