Journal
CELL REPORTS
Volume 40, Issue 13, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2022.111404
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Funding
- AIRC [20566, 20240]
- FPRC 5xmille 2018 Ministero Salute, project ADVANCE/A-Bi-C: Italian Ministry of Health, Ricerca Corrente
- Compagnia di San Paolo
- Royal College of Surgeons of England/Cancer Research UK Clinician Scientist Fellowship [C19198/A15339]
- Urology Foundation and John Black Charitable Foundation
- Royal College of Surgeons of England [PO117626]
- Barts Charity [MGU0533]
- Orchid Charity
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FOXA1 plays a key role in dysregulation of alternative splicing in prostate cancer by controlling transcription factor expression and binding to splicing-related genes, leading to the production of dominant isoforms and influencing patient survival.
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 definitionmechanism calibrating alter-native 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 land-scape 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.
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