2. Academic Validation
  3. METTL13 Methylation of eEF1A Increases Translational Output to Promote Tumorigenesis

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.
Shuo Liu 1,  Simone Hausmann 2,  Scott Moore Carlson 1,  Mary Esmeralda Fuentes 2,  Joel William Francis 1,  Renjitha Pillai 3,  Shane Michael Lofgren 2,  Laura Hulea 4,  Kristofferson Tandoc 4,  Jiuwei Lu 5,  Ami Li 6,  Nicholas Dang Nguyen 2,  Marcello Caporicci 2,  Michael Paul Kim 7,  Anirban Maitra 8,  Huamin Wang 9,  Ignacio Ivan Wistuba 10,  John Anthony Porco Jr 11,  Michael Cory Bassik 6,  Joshua Eric Elias 12,  Jikui Song 5,  Ivan Topisirovic 4,  Capucine Van Rechem 3,  Pawel Karol Mazur 13,  Or Gozani 14
Affiliations

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: [email protected].
  • 14 Department of Biology, Stanford University, Stanford, CA 94305, USA. Electronic address: [email protected].
PMID: 30612740 DOI: 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.

Keywords

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

Figures