METTL13 Methylation of eEF1A Increases Translational Output to Promote Tumorigenesis

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 tumori...

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Published in:	Cell Vol. 176; no. 3; pp. 491 - 504.e21
Main 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, Li, Ami, Nguyen, Nicholas Dang, Caporicci, Marcello, Kim, Michael Paul, Maitra, Anirban, Wang, Huamin, Wistuba, Ignacio Ivan, Porco, John Anthony, Bassik, Michael Cory, Elias, Joshua Eric, Song, Jikui, Topisirovic, Ivan, Van Rechem, Capucine, Mazur, Pawel Karol, Gozani, Or
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 24-01-2019
Subjects:	Adult Aged Animals Carcinogenesis Cell Line Cell Transformation, Neoplastic - metabolism eEF1A Female HEK293 Cells Heterografts Humans lung cancer Lysine - metabolism lysine methylation Male Methylation Methyltransferases - genetics Methyltransferases - metabolism METTL13 Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic pancreatic cancer Pancreatic Neoplasms - genetics Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - pathology Peptide Elongation Factor 1 - genetics Peptide Elongation Factor 1 - metabolism Protein Biosynthesis protein methylation Protein Processing, Post-Translational Proteomics RAS Signal Transduction translation translation elongation lung cancer pancreatic cancer METTL13 RAS protein methylation translation eEF1A lysine methylation translation elongation
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Summary:	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. [Display omitted] •METTL13 is the physiologic eEF1A lysine 55 dimethyltransferase•METTL13 dimethylation of eEF1A stimulates protein synthesis in cancer cells•The METTL13-eEF1A methylation axis fuels Ras-driven tumorigenesis in vivo•METTL13 depletion sensitizes cancer cells to PI3K and mTOR pathway inhibitors Ras-driven cancers ramp up protein synthesis by increasing the GTPase activity of a translation elongation factor through a mechanism that involves METTL13-catalyzed eEF1A dimethylation
Bibliography:	AUTHOR CONTRIBUTIONS S.L. and S.H. contributed equally to this work. They were responsible for the experimental design, execution, data analysis, and manuscript preparation. M.E.F, J.W.F, and M.C. helped S.L. and S.H. with experimental design and execution. S.L. and R.P. performed the polysome profiling experiments and C.V.R. supervised. L.H., K.T., I.T. and J.A.P. performed SDS-1-021 experiments. N.D.N. contributed to MRI analysis. S.M.L. performed bioinformatic meta-analysis of gene expression and survival. I.I.W and H.W. performed pathologic and histological analyses. A.M. and M.P.K provided PDX samples. S.L. performed and analyzed the mass spectrometry experiments, with help from J.E.E.. S.M.C. generated the KMT sgRNA library with help from A.L. and M.C.B. and S.M.C. generated the lysate library. J.L. and J.S. provided the structural model. I.T. helped with manuscript preparation. O.G. and P.K.M. were equally responsible for supervision of research, data interpretation and manuscript preparation.
ISSN:	0092-8674 1097-4172
DOI:	10.1016/j.cell.2018.11.038