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Sungyun Cho1,10, Gina Lee1,2,10,*, Brian F. Pickering1,10, Cholsoon Jang3,4, Jin H. Park1, Long He1, Lavina Mathur2, Seung-Soo Kim5, Sunhee Jung4, Hong-Wen Tang6,7, Sebastien Monette8, Joshua D. Rabinowitz3, Norbert Perrimon6,9, Samie R. Jaffrey1,*, John Blenis1,11,*
1Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medicine, Cornell University, New York, NY, USA
2Department of Microbiology and Molecular Genetics, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Irvine, CA, USA
3Department of Chemistry, Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA
4Department of Biological Chemistry, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Irvine, CA, USA
5Department of Obstetrics and Gynecology, Irving Medical Center, Columbia University, New York, NY, USA
6Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
7Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore
8Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, The Rockefeller University, Weill Cornell Medicine, New York, NY, USA
9Howard Hughes Medical Institute, Boston, MA, USA
10These authors contributed equally.
11Lead contact
*Corresponding author
Abstract
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.
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