METTL13 Methylation of eEF1A Increases Translational Output to Promote Tumorigenesis.
Adult
Aged
Animals
Carcinogenesis
Cell Line
Cell Transformation, Neoplastic
/ metabolism
Female
HEK293 Cells
Heterografts
Humans
Lysine
/ metabolism
Male
Methylation
Methyltransferases
/ genetics
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Pancreatic Neoplasms
/ genetics
Peptide Elongation Factor 1
/ genetics
Protein Biosynthesis
Protein Processing, Post-Translational
Proteomics
Signal Transduction
METTL13
RAS
eEF1A
lung cancer
lysine methylation
pancreatic cancer
protein methylation
translation
translation elongation
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
24 01 2019
24 01 2019
Historique:
received:
17
08
2018
revised:
18
10
2018
accepted:
21
11
2018
pubmed:
8
1
2019
medline:
27
11
2019
entrez:
8
1
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30612740
pii: S0092-8674(18)31563-0
doi: 10.1016/j.cell.2018.11.038
pmc: PMC6499081
mid: NIHMS1515402
pii:
doi:
Substances chimiques
EEF1A1 protein, human
0
Peptide Elongation Factor 1
0
EEF1AKNMT protein, human
EC 2.1.1.-
Methyltransferases
EC 2.1.1.-
Lysine
K3Z4F929H6
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
491-504.e21Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM118173
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NICHD NIH HHS
ID : DP2 HD084069
Pays : United States
Organisme : NCI NIH HHS
ID : K08 CA218690
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM079641
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA070907
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM119721
Pays : United States
Organisme : NCI NIH HHS
ID : R00 CA197816
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA202021
Pays : United States
Organisme : NCI NIH HHS
ID : K99 CA190803
Pays : United States
Informations de copyright
Copyright © 2018 Elsevier Inc. All rights reserved.
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