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1.
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
2.
Cell ; 173(7): 1742-1754.e17, 2018 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-29906449

RESUMO

Osmotic diarrhea is a prevalent condition in humans caused by food intolerance, malabsorption, and widespread laxative use. Here, we assess the resilience of the gut ecosystem to osmotic perturbation at multiple length and timescales using mice as model hosts. Osmotic stress caused reproducible extinction of highly abundant taxa and expansion of less prevalent members in human and mouse microbiotas. Quantitative imaging revealed decimation of the mucus barrier during osmotic perturbation, followed by recovery. The immune system exhibited temporary changes in cytokine levels and a lasting IgG response against commensal bacteria. Increased osmolality prevented growth of commensal strains in vitro, revealing one mechanism contributing to extinction. Environmental availability of microbiota members mitigated extinction events, demonstrating how species reintroduction can affect community resilience. Our findings (1) demonstrate that even mild osmotic diarrhea can cause lasting changes to the microbiota and host and (2) lay the foundation for interventions that increase system-wide resilience.


Assuntos
Diarreia/patologia , Microbioma Gastrointestinal/efeitos dos fármacos , Polietilenoglicóis/farmacologia , Animais , Bacteroidetes/efeitos dos fármacos , Bacteroidetes/genética , Bacteroidetes/isolamento & purificação , Ceco/química , Ceco/metabolismo , Ceco/microbiologia , Ceco/patologia , Colo/química , Colo/microbiologia , Colo/patologia , Citocinas/metabolismo , Diarreia/imunologia , Diarreia/microbiologia , Diarreia/veterinária , Fezes/microbiologia , Glicosídeo Hidrolases/metabolismo , Humanos , Imunidade Humoral/efeitos dos fármacos , Imunoglobulina G/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Metagenômica , Camundongos , Concentração Osmolar , Polietilenoglicóis/metabolismo , Proteoma/análise , RNA Ribossômico 16S/química , RNA Ribossômico 16S/genética , Verrucomicrobia/efeitos dos fármacos , Verrucomicrobia/genética , Verrucomicrobia/isolamento & purificação
3.
Cancer Cell ; 37(6): 834-849.e13, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32442403

RESUMO

Molecular mechanisms underlying adaptive targeted therapy resistance in pancreatic ductal adenocarcinoma (PDAC) are poorly understood. Here, we identify SETD5 as a major driver of PDAC resistance to MEK1/2 inhibition (MEKi). SETD5 is induced by MEKi resistance and its deletion restores refractory PDAC vulnerability to MEKi therapy in mouse models and patient-derived xenografts. SETD5 lacks histone methyltransferase activity but scaffolds a co-repressor complex, including HDAC3 and G9a. Gene silencing by the SETD5 complex regulates known drug resistance pathways to reprogram cellular responses to MEKi. Pharmacological co-targeting of MEK1/2, HDAC3, and G9a sustains PDAC tumor growth inhibition in vivo. Our work uncovers SETD5 as a key mediator of acquired MEKi therapy resistance in PDAC and suggests a context for advancing MEKi use in the clinic.


Assuntos
Cromatina/genética , Resistencia a Medicamentos Antineoplásicos , Metiltransferases/metabolismo , Terapia de Alvo Molecular , Neoplasias Pancreáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Apoptose , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Proliferação de Células , Feminino , Antígenos de Histocompatibilidade/genética , Antígenos de Histocompatibilidade/metabolismo , Histona Desacetilases/química , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 1/genética , MAP Quinase Quinase 1/metabolismo , MAP Quinase Quinase 2/antagonistas & inibidores , MAP Quinase Quinase 2/genética , MAP Quinase Quinase 2/metabolismo , Metiltransferases/antagonistas & inibidores , Metiltransferases/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Piridonas/farmacologia , Pirimidinonas/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
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