METTL13 Methylation of eEF1A Increases Translational Output to Promote Tumorigenesis

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; Nicholas Dang Nguyen; Marcello Caporicci; Michael Paul Kim; Anirban Maitra; Huamin Wang; Ignacio Ivan Wistuba; John Anthony Porco Jr; Michael Cory Bassik; Joshua Eric Elias; Jikui Song; Ivan Topisirovic; Capucine Van Rechem; Pawel Karol Mazur; Or Gozani

doi:10.1016/j.cell.2018.11.038

METTL13 Methylation of eEF1A Increases Translational Output to Promote Tumorigenesis

Cell. 2019 Jan 24;176(3):491-504.e21. doi: 10.1016/j.cell.2018.11.038. Epub 2019 Jan 3.

Authors

Shuo Liu¹, Simone Hausmann², Scott Moore Carlson¹, Mary Esmeralda Fuentes², Joel William Francis¹, Renjitha Pillai³, Shane Michael Lofgren², Laura Hulea⁴, Kristofferson Tandoc⁴, Jiuwei Lu⁵, Ami Li⁶, Nicholas Dang Nguyen², Marcello Caporicci², Michael Paul Kim⁷, Anirban Maitra⁸, Huamin Wang⁹, Ignacio Ivan Wistuba¹⁰, John Anthony Porco Jr¹¹, Michael Cory Bassik⁶, Joshua Eric Elias¹², Jikui Song⁵, Ivan Topisirovic⁴, Capucine Van Rechem³, Pawel Karol Mazur¹³, Or Gozani¹⁴

Affiliations

¹ Department of Biology, Stanford University, Stanford, CA 94305, USA.
² Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
³ Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁴ Lady Davis Institute and Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H3T 1E2, Canada.
⁵ Department of Biochemistry, University of California, Riverside, Riverside, CA 92521, USA.
⁶ Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁷ Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁸ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁹ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁰ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹¹ Department of Chemistry, Boston University, Boston, MA 02215, USA.
¹² Deparment of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹³ Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: pkmazur@mdanderson.org.
¹⁴ Department of Biology, Stanford University, Stanford, CA 94305, USA. Electronic address: ogozani@stanford.edu.

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.

Keywords: METTL13; RAS; eEF1A; lung cancer; lysine methylation; pancreatic cancer; protein methylation; translation; translation elongation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adult
Aged
Animals
Carcinogenesis
Cell Line
Cell Transformation, Neoplastic / metabolism
Female
HEK293 Cells
Heterografts
Humans
Lysine / metabolism
Male
Methylation
Methyltransferases / genetics
Methyltransferases / metabolism*
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Pancreatic Neoplasms / genetics
Pancreatic Neoplasms / metabolism
Pancreatic Neoplasms / pathology
Peptide Elongation Factor 1 / genetics
Peptide Elongation Factor 1 / metabolism*
Protein Biosynthesis
Protein Processing, Post-Translational
Proteomics
Signal Transduction

Substances

EEF1A1 protein, human
Peptide Elongation Factor 1
EEF1AKNMT protein, human
Methyltransferases
Lysine

Abstract

Publication types

MeSH terms

Substances

Grants and funding