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Functional significance of U2AF1 S34F mutations in lung adenocarcinomas.
Esfahani, Mohammad S; Lee, Luke J; Jeon, Young-Jun; Flynn, Ryan A; Stehr, Henning; Hui, Angela B; Ishisoko, Noriko; Kildebeck, Eric; Newman, Aaron M; Bratman, Scott V; Porteus, Matthew H; Chang, Howard Y; Alizadeh, Ash A; Diehn, Maximilian.
Afiliação
  • Esfahani MS; Stanford Cancer Institute, Stanford University, Stanford, USA.
  • Lee LJ; Division of Oncology, Department of Medicine, Stanford University, Stanford, USA.
  • Jeon YJ; Department of Radiation Oncology, Stanford University, Stanford, USA.
  • Flynn RA; Stanford Cancer Institute, Stanford University, Stanford, USA.
  • Stehr H; Stanford Cancer Institute, Stanford University, Stanford, USA.
  • Hui AB; Department of Radiation Oncology, Stanford University, Stanford, USA.
  • Ishisoko N; Department of Chemistry, Stanford University, Stanford, USA.
  • Kildebeck E; Stanford Cancer Institute, Stanford University, Stanford, USA.
  • Newman AM; Department of Pathology, Stanford University, Stanford, CA, USA.
  • Bratman SV; Stanford Cancer Institute, Stanford University, Stanford, USA.
  • Porteus MH; Department of Radiation Oncology, Stanford University, Stanford, USA.
  • Chang HY; Department of Bioengineering, Stanford University, Stanford, USA.
  • Alizadeh AA; Department of Pediatrics, Stanford University, Stanford, USA.
  • Diehn M; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, USA.
Nat Commun ; 10(1): 5712, 2019 12 13.
Article em En | MEDLINE | ID: mdl-31836708
ABSTRACT
The functional role of U2AF1 mutations in lung adenocarcinomas (LUADs) remains incompletely understood. Here, we report a significant co-occurrence of U2AF1 S34F mutations with ROS1 translocations in LUADs. To characterize this interaction, we profiled effects of S34F on the transcriptome-wide distribution of RNA binding and alternative splicing in cells harboring the ROS1 translocation. Compared to its wild-type counterpart, U2AF1 S34F preferentially binds and modulates splicing of introns containing CAG trinucleotides at their 3' splice junctions. The presence of S34F caused a shift in cross-linking at 3' splice sites, which was significantly associated with alternative splicing of skipped exons. U2AF1 S34F induced expression of genes involved in the epithelial-mesenchymal transition (EMT) and increased tumor cell invasion. Finally, S34F increased splicing of the long over the short SLC34A2-ROS1 isoform, which was also associated with enhanced invasiveness. Taken together, our results suggest a mechanistic interaction between mutant U2AF1 and ROS1 in LUAD.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas de Fusão Oncogênica / Processamento Alternativo / Fator de Processamento U2AF / Adenocarcinoma de Pulmão / Neoplasias Pulmonares Idioma: En Ano de publicação: 2019 Tipo de documento: Article
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas de Fusão Oncogênica / Processamento Alternativo / Fator de Processamento U2AF / Adenocarcinoma de Pulmão / Neoplasias Pulmonares Idioma: En Ano de publicação: 2019 Tipo de documento: Article