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.

FOXA1 regulates alternative splicing in prostate cancer / M. Del Giudice, J.G. Foster, S. Peirone, A. Rissone, L. Caizzi, F. Gaudino, C. Parlato, F. Anselmi, R. Arkell, S. Guarrera, S. Oliviero, G. Basso, P. Rajan, M. Cereda. - In: CELL REPORTS. - ISSN 2211-1247. - 40:13(2022), pp. 111404.1-111404.25. [10.1016/j.celrep.2022.111404]

FOXA1 regulates alternative splicing in prostate cancer

S. Peirone
Secondo
;
M. Cereda
Ultimo
2022

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.
FOXA1; alternative splicing; prostate cancer; splicing factors; HNRNPK; SRSF1; nonsense-mediated decay; poison exons; FLNA; biomarkers
Settore BIO/11 - Biologia Molecolare
Settore MED/06 - Oncologia Medica
Settore MED/03 - Genetica Medica
FON_NAZ21MCERE_01 - Deciphering alternative splicing deregulation in cancer to identify novel therapeutic targets (4° anno-portabilità) - CEREDA, MATTEO - FON_NAZ - Bandi Altre Fondazioni - 2021
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/938955
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