AKT3-mediated IWS1 phosphorylation promotes the proliferation of EGFR-mutant lung adenocarcinomas through cell...

Area of Science:

• Molecular Biology
• Cancer Research
• Epigenetics

Background:

• Alternative RNA splicing is crucial for cellular function and often dysregulated in cancer.
• The protein IWS1 (Intercellular Washout 1) and its phosphorylation status are implicated in gene regulation.
• Aberrant RNA splicing contributes to lung adenocarcinoma development and progression.

Purpose of the Study:

• To elucidate the mechanism by which AKT-phosphorylated IWS1 regulates alternative RNA splicing in lung cancer.
• To identify the downstream targets and consequences of IWS1-mediated splicing.
• To investigate the clinical relevance of this pathway in human lung adenocarcinomas.

Main Methods:

• RNA sequencing (RNA-seq) was performed on lung adenocarcinoma cells.
• Investigated the role of LEDGF/SRSF1 splicing complexes and histone modifications (H3K36me3).
• Analyzed U2AF2 mRNA variants, U2AF65 protein function, and CDCA5/Sororin expression in cell lines and human tumors.

Main Results:

• Lack of phosphorylated IWS1 led to an exon 2-deficient U2AF2 splice variant.
• U2AF2 exon 2 inclusion is cell cycle-dependent, regulated by LEDGF/SRSRSF1 complexes.
• This process involves IWS1-dependent histone H3K36me3 deposition, affecting Sororin levels and downstream signaling (ERK, G2/M arrest).

Conclusions:

• The IWS1 phosphorylation pathway regulates U2AF2 alternative splicing, impacting Sororin expression and cell proliferation.
• This pathway is active in EGFR-mutant lung adenocarcinomas.
• Pathway activation correlates with advanced tumor stage, poor prognosis, and relapse, highlighting its clinical significance.