The androgen receptor couples promoter recruitment of RNA processing factors to regulation of alternative polyadenylation at the 3' end of transcripts.
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
23 09 2022
23 09 2022
Historique:
accepted:
29
08
2022
revised:
20
07
2022
received:
05
12
2021
pubmed:
1
9
2022
medline:
28
9
2022
entrez:
31
8
2022
Statut:
ppublish
Résumé
Prostate cancer (PC) relies on androgen receptor (AR) signaling. While hormonal therapy (HT) is efficacious, most patients evolve to an incurable castration-resistant stage (CRPC). To date, most proposed mechanisms of acquired resistance to HT have focused on AR transcriptional activity. Herein, we uncover a new role for the AR in alternative cleavage and polyadenylation (APA). Inhibition of the AR by Enzalutamide globally regulates APA in PC cells, with specific enrichment in genes related to transcription and DNA topology, suggesting their involvement in transcriptome reprogramming. AR inhibition selects promoter-distal polyadenylation sites (pAs) enriched in cis-elements recognized by the cleavage and polyadenylation specificity factor (CPSF) complex. Conversely, promoter-proximal intronic pAs relying on the cleavage stimulation factor (CSTF) complex are repressed. Mechanistically, Enzalutamide induces rearrangement of APA subcomplexes and impairs the interaction between CPSF and CSTF. AR inhibition also induces co-transcriptional CPSF recruitment to gene promoters, predisposing the selection of pAs depending on this complex. Importantly, the scaffold CPSF160 protein is up-regulated in CRPC cells and its depletion represses HT-induced APA patterns. These findings uncover an unexpected role for the AR in APA regulation and suggest that APA-mediated transcriptome reprogramming represents an adaptive response of PC cells to HT.
Identifiants
pubmed: 36043441
pii: 6679404
doi: 10.1093/nar/gkac737
pmc: PMC9508809
doi:
Substances chimiques
Benzamides
0
Cleavage And Polyadenylation Specificity Factor
0
Cleavage Stimulation Factor
0
Nitriles
0
Receptors, Androgen
0
Phenylthiohydantoin
2010-15-3
enzalutamide
93T0T9GKNU
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
9780-9796Subventions
Organisme : NCI NIH HHS
ID : P30 CA010815
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM084089
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM129069
Pays : United States
Informations de copyright
© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.
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