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

N 6-adenosine methylation (m6A) is the most abundant mRNA modification that controls gene expression through 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)- 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 protein 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 via a 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. ### Competing Interest Statement The authors have declared no competing interest. * Bcl-2 : (B-cell lymphoma 2) PHLPP2 : (PH domain and leucine-rich repeat protein phosphatase 2) LAM : (Lymphangioleiomyomatosis) TSC : (Tuberous sclerosis complex) miCLIP-seq : (m6A individual-nucleotide resolution UV crosslinking and immunoprecipitation) BEX1 : (Brain expressed X-linked 1) EIF4A2 : (Eukaryotic translation initiation factor 4A2) EIF6 : (Eukaryotic translation initiation factor 6) FGFR : (Fibroblast growth factor receptor) NABP1 : (Nucleic acid binding protein 1) NOP56 : (NOP56 ribonucleoprotein) OBSCN : (Obscurin) PKD : (Polycystic kidney disease) PRPF4B : (Pre-mRNA processing factor 4B) SDF2 : (Stromal cell-derived factor 2) SLC25A37 : (Solute carrier family 25 member 37) STAT5B : (Signal transducer and activator of transcription 5B) TRDMT1 : (tRNA aspartic acid methyltransferase 1) TRP : (Transient receptor potential) ERK : (Extracellular signal-regulated kinase) PI3K : (Phosphoinositide 3-kinase).