METTL13 methylation of eEF1A increases translational output to promote tumorigenesis
Files
Accepted manuscript
Supporting documentation
Date
2019-01-24
Authors
Liu, Shuo
Hausmann, Simone
Carlson, Scott Moore
Fuentes, Mary Esmeralda
Francis, Joel William
Pillai, Renjitha
Lofgren, Shane Michael
Hulea, Laura
Tandoc, Kristofferson
Lu, Jiuwei
Version
Supporting documentation
Accepted manuscript
Accepted manuscript
OA Version
Citation
Shuo Liu, Simone Hausmann, Scott Moore Carlson, Mary Esmeralda Fuentes, Joel William Francis, Renjitha Pillai, Shane Michael Lofgren, Laura Hulea, Kristofferson Tandoc, Jiuwei Lu, Ami Li, Dang Nguyen Nicholas, Marcello Caporicci, Michael Paul Kim, Anirban Maitra, Huamin Wang, Ignacio Ivan Wistuba, John Anthony Porco, Michael Cory Bassik, Joshua Eric Elias, Jikui Song, Ivan Topisirovic, Capucine Van Rechem, Pawel Karol Mazur, Or Gozani. 2019. "METTL13 Methylation of eEF1A Increases Translational Output to Promote Tumorigenesis." CELL, Volume 176, Issue 3, pp. 491 - + (35). https://doi.org/10.1016/j.cell.2018.11.038
Abstract
Increased protein synthesis plays an etiologic role in diverse cancers. Here, we demonstrate that METTL13 (methyltransferase-like 13) dimethylation of eEF1A (eukaryotic elongation factor 1A) lysine 55 (eEF1AK55me2) is utilized by Ras-driven cancers to increase translational output and promote tumorigenesis in vivo. METTL13-catalyzed eEF1A methylation increases eEF1A's intrinsic GTPase activity in vitro and protein production in cells. METTL13 and eEF1AK55me2 levels are upregulated in cancer and negatively correlate with pancreatic and lung cancer patient survival. METTL13 deletion and eEF1AK55me2 loss dramatically reduce Ras-driven neoplastic growth in mouse models and in patient-derived xenografts (PDXs) from primary pancreatic and lung tumors. Finally, METTL13 depletion renders PDX tumors hypersensitive to drugs that target growth-signaling pathways. Together, our work uncovers a mechanism by which lethal cancers become dependent on the METTL13-eEF1AK55me2 axis to meet their elevated protein synthesis requirement and suggests that METTL13 inhibition may constitute a targetable vulnerability of tumors driven by aberrant Ras signaling.