mTORC1 promotes cell growth via m6A-dependent mRNA degradation

Dysregulated mTORC1 signaling alters a wide range of cellular processes, contributing to metabolic disorders and cancer. Defining the molecular details of downstream effectors is thus critical for uncovering selective therapeutic targets. We report that mTORC1 and its downstream kinase S6K enhance eIF4A/4B-mediated translation of Wilms’ tumor 1-associated protein (WTAP), an adaptor for the N(6)-methyladenosine (m(6)A) RNA methyltransferase complex. This regulation is mediated by 5’UTR of WTAP mRNA that is targeted by eIF4A/4B. Single nucleotide-resolution m(6)A mapping revealed that MAX dimerization protein 2 (MXD2) mRNA contains m(6)A, and increased m(6)A modification enhances its degradation. WTAP induces cMyc-MAX association by suppressing MXD2 expression, which promotes cMyc transcriptional activity and proliferation of mTORC1-activated cancer cells. These results elucidate a mechanism whereby mTORC1 stimulates oncogenic signaling via m(6)A RNA modification and illuminates WTAP-MXD2-cMyc axis as a potential therapeutic target for mTORC1-driven cancers.