1. FOXA1 regulates alternative splicing in prostate cancer.
- Author
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Del Giudice M, Foster JG, Peirone S, Rissone A, Caizzi L, Gaudino F, Parlato C, Anselmi F, Arkell R, Guarrera S, Oliviero S, Basso G, Rajan P, and Cereda M
- Subjects
- Chromatin, Hepatocyte Nuclear Factor 3-alpha genetics, Hepatocyte Nuclear Factor 3-alpha metabolism, Humans, Male, Neoplasm Recurrence, Local, RNA Splicing Factors metabolism, Serine-Arginine Splicing Factors metabolism, Trans-Activators metabolism, Alternative Splicing genetics, Prostatic Neoplasms genetics
- Abstract
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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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