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Cell ; 176(3): 491-504.e21, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30612740

RESUMO

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.


Assuntos
Metiltransferases/metabolismo , Fator 1 de Elongação de Peptídeos/metabolismo , Adulto , Idoso , Animais , Carcinogênese , Linhagem Celular , Transformação Celular Neoplásica/metabolismo , Feminino , Células HEK293 , Xenoenxertos , Humanos , Lisina/metabolismo , Masculino , Metilação , Metiltransferases/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Fator 1 de Elongação de Peptídeos/genética , Biossíntese de Proteínas , Processamento de Proteína Pós-Traducional , Proteômica , Transdução de Sinais
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