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 N6-methyladenosine (m6A) RNA methyltransferase complex. This regulation is mediated by 5′ UTR of WTAP mRNA that is targeted by eIF4A/4B. Single-nucleotide-resolution m6A mapping revealed that MAX dimerization protein 2 (MXD2) mRNA contains m6A, and increased m6A 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 m6A RNA modification and illuminates the WTAP-MXD2-cMyc axis as a potential therapeutic target for mTORC1-driven cancers. [Display omitted] •mTORC1 induces WTAP translation through eIF4A/4B•mTORC1-WTAP increases global m6A levels on mRNA•Increased m6A modification by mTORC1 destabilizes mRNAs•mTORC1 decreases mRNA expression of MXD2, cMyc suppressor, through m6A modification Cho et al. report that mTORC1 enhances WTAP translation through eIF4A/4B, resulting in the increase of global mRNA m6A modification. m6A modification of mRNAs by mTORC1 destabilizes transcripts through YTHDF m6A-reader proteins. Among the targets, mTORC1 increases m6A modification on MXD2 mRNA, cMyc suppressor, resulting in increased cMyc activity and tumor growth.