論文 - 詳細
RRC ID | 65153 |
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著者 | Liu S, Hausmann S, Carlson SM, Fuentes ME, Francis JW, Pillai R, Lofgren SM, Hulea L, Tandoc K, Lu J, Li A, Nguyen ND, Caporicci M, Kim MP, Maitra A, Wang H, Wistuba II, Porco JA Jr, Bassik MC, Elias JE, Song J, Topisirovic I, Van Rechem C, Mazur PK, Gozani O. |
タイトル | METTL13 Methylation of eEF1A Increases Translational Output to Promote Tumorigenesis. |
ジャーナル | Cell |
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. |
巻・号 | 176(3) |
ページ | 491-504.e21 |
公開日 | 2019-1-24 |
DOI | 10.1016/j.cell.2018.11.038 |
PII | S0092-8674(18)31563-0 |
PMID | 30612740 |
PMC | PMC6499081 |
MeSH | 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 |
IF | 38.637 |
リソース情報 | |
ヒト・動物細胞 | T3M-4(RCB1021) |