FOXA1 regulates alternative splicing in prostate cancer

Cell Rep. 2022 Sep 27;40(13):111404. doi: 10.1016/j.celrep.2022.111404.


Dysregulation of alternative splicing in prostate cancer is linked to transcriptional programs activated by AR, ERG, FOXA1, and MYC. Here, we show that FOXA1 functions as the primary orchestrator of alternative splicing dysregulation across 500 primary and metastatic prostate cancer transcriptomes. We demonstrate that FOXA1 binds to the regulatory regions of splicing-related genes, including HNRNPK and SRSF1. By controlling trans-acting factor expression, FOXA1 exploits an "exon definition" mechanism calibrating alternative splicing toward dominant isoform production. This regulation especially impacts splicing factors themselves and leads to a reduction of nonsense-mediated decay (NMD)-targeted isoforms. Inclusion of the NMD-determinant FLNA exon 30 by FOXA1-controlled oncogene SRSF1 promotes cell growth in vitro and predicts disease recurrence. Overall, we report a role for FOXA1 in rewiring the alternative splicing landscape in prostate cancer through a cascade of events from chromatin access, to splicing factor regulation, and, finally, to alternative splicing of exons influencing patient survival.

Keywords: CP: Cancer; CP: Molecular biology; FLNA; FOXA1; HNRNPK; SRSF1; alternative splicing; biomarkers; nonsense-mediated decay; poison exons; prostate cancer; splicing factors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing* / genetics
  • Chromatin
  • Hepatocyte Nuclear Factor 3-alpha / genetics
  • Hepatocyte Nuclear Factor 3-alpha / metabolism
  • Humans
  • Male
  • Neoplasm Recurrence, Local
  • Prostatic Neoplasms* / genetics
  • RNA Splicing Factors / metabolism
  • Serine-Arginine Splicing Factors / metabolism
  • Trans-Activators / metabolism


  • Chromatin
  • FOXA1 protein, human
  • Hepatocyte Nuclear Factor 3-alpha
  • RNA Splicing Factors
  • SRSF1 protein, human
  • Trans-Activators
  • Serine-Arginine Splicing Factors