FOXA1 regulates alternative splicing in prostate cancer

Area of Science:

• Molecular Biology
• Cancer Genomics
• RNA Biology

Background:

• Alternative splicing dysregulation is implicated in prostate cancer pathogenesis.
• Transcriptional programs involving AR, ERG, FOXA1, and MYC are linked to these splicing alterations.

Purpose of the Study:

• To identify the primary orchestrator of alternative splicing dysregulation in prostate cancer.
• To elucidate the mechanisms by which FOXA1 influences alternative splicing and its impact on disease progression.

Main Methods:

• Analysis of 500 primary and metastatic prostate cancer transcriptomes.
• Chromatin immunoprecipitation to identify FOXA1 binding sites.
• Assessment of splicing factor expression and exon inclusion patterns.
• In vitro cell growth assays and correlation with clinical outcomes.

Main Results:

• FOXA1 acts as the primary regulator of alternative splicing dysregulation in prostate cancer.
• FOXA1 binds to regulatory regions of splicing factors like HNRNPK and SRSF1.
• FOXA1 promotes dominant isoform production via an "exon definition" mechanism, reducing nonsense-mediated decay (NMD)-targeted isoforms.
• SRSF1, controlled by FOXA1, drives inclusion of the FLNA exon 30, promoting cell growth and predicting recurrence.

Conclusions:

• FOXA1 plays a critical role in rewiring the alternative splicing landscape in prostate cancer.
• This rewiring involves chromatin access, splicing factor regulation, and altered exon splicing.
• FOXA1-mediated alternative splicing changes, particularly FLNA exon 30 inclusion, are linked to prostate cancer progression and patient survival.