AKT3-mediated IWS1 phosphorylation promotes the proliferation of EGFR-mutant lung adenocarcinomas through cell cycle-regulated U2AF2 RNA splicing

Nat Commun. 2021 Jul 30;12(1):4624. doi: 10.1038/s41467-021-24795-1.

Abstract

AKT-phosphorylated IWS1 regulates alternative RNA splicing via a pathway that is active in lung cancer. RNA-seq studies in lung adenocarcinoma cells lacking phosphorylated IWS1, identified a exon 2-deficient U2AF2 splice variant. Here, we show that exon 2 inclusion in the U2AF2 mRNA is a cell cycle-dependent process that is regulated by LEDGF/SRSF1 splicing complexes, whose assembly is controlled by the IWS1 phosphorylation-dependent deposition of histone H3K36me3 marks in the body of target genes. The exon 2-deficient U2AF2 mRNA encodes a Serine-Arginine-Rich (RS) domain-deficient U2AF65, which is defective in CDCA5 pre-mRNA processing. This results in downregulation of the CDCA5-encoded protein Sororin, a phosphorylation target and regulator of ERK, G2/M arrest and impaired cell proliferation and tumor growth. Analysis of human lung adenocarcinomas, confirmed activation of the pathway in EGFR-mutant tumors and showed that pathway activity correlates with tumor stage, histologic grade, metastasis, relapse after treatment, and poor prognosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Adenocarcinoma of Lung / genetics*
  • Adenocarcinoma of Lung / metabolism
  • Animals
  • Cell Cycle / genetics*
  • Cell Line, Tumor
  • Cell Proliferation / genetics*
  • ErbB Receptors / genetics*
  • ErbB Receptors / metabolism
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Humans
  • Kaplan-Meier Estimate
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Mutation
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / genetics*
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Splicing
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism
  • Splicing Factor U2AF / genetics*
  • Splicing Factor U2AF / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism

Substances

  • Iws1 protein, human
  • RNA-Binding Proteins
  • Splicing Factor U2AF
  • Transcription Factors
  • U2AF2 protein, human
  • ErbB Receptors
  • Proto-Oncogene Proteins c-akt