期刊
CELL
卷 176, 期 3, 页码 491-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2018.11.038
关键词
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资金
- NIH [K99CA190803, 5K08CA218690-02, R35GM118173, 1DP2HD084069-01, 1R35GM119721, R01CA202021, R00CA197816, P50CA070907, P30CA016672, R01GM079641]
- Stanford ChEM-H
- MD Anderson Moonshot Program
- Neuroendocrine Tumor Research Foundation
- American Association for Cancer Research
- Deutsche Forschungsgemeinschaft Postdoctoral Fellowship
- [5T32GM007276]
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 upregu-lated 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.
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