Circular RNAs add diversity to androgen receptor isoform repertoire in castration-resistant prostate cancer.
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
11 2019
11 2019
Historique:
received:
11
05
2019
accepted:
03
06
2019
pubmed:
15
8
2019
medline:
3
3
2020
entrez:
15
8
2019
Statut:
ppublish
Résumé
Deregulated expression of circular RNAs (circRNAs) is associated with various human diseases, including many types of cancer. Despite their growing links to cancer, there has been limited characterization of circRNAs in metastatic castration-resistant prostate cancer, the major cause of prostate cancer mortality. Here, through the analysis of an exome-capture RNA-seq dataset from 47 metastatic castration-resistant prostate cancer samples and ribodepletion and RNase R RNA-sequencing of patient-derived xenografts (PDXs) and cell models, we identified 13 circRNAs generated from the key prostate cancer driver gene-androgen receptor (AR). We validated and characterized the top four most abundant, clinically relevant AR circRNAs. Expression of these AR circRNAs was upregulated during castration-resistant progression of PDXs. The upregulation was not due to global increase of circRNA formation in these tumors. Instead, the levels of AR circRNAs correlated strongly with that of the linear AR transcripts (both AR and AR variants) in clinical samples and PDXs, indicating a transcriptional mechanism of regulation. In cultured cells, androgen suppressed the expression of these AR circRNAs and the linear AR transcripts, and the suppression was attenuated by an antiandrogen. Using nuclear/cytoplasmic fractionation and RNA in-situ hybridization assays, we demonstrated predominant cytoplasmic localization of these AR circRNAs, indicating likely cytoplasmic functions. Overall, this is the first comprehensive characterization of circRNAs arising from the AR gene. With greater resistance to exoribonuclease compared to the linear AR transcripts and detectability of AR circRNAs in patient plasma, these AR circRNAs may serve as surrogate circulating markers for AR/AR-variant expression and castration-resistant prostate cancer progression.
Identifiants
pubmed: 31409897
doi: 10.1038/s41388-019-0947-7
pii: 10.1038/s41388-019-0947-7
pmc: PMC6842090
mid: NIHMS1531108
doi:
Substances chimiques
AR protein, human
0
Protein Isoforms
0
RNA, Circular
0
Receptors, Androgen
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
7060-7072Subventions
Organisme : NCI NIH HHS
ID : P50 CA097186
Pays : United States
Organisme : NIDCR NIH HHS
ID : R21 DE017008
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI101046
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA236549
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI106676
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA243793
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM103424
Pays : United States
Organisme : NIMHD NIH HHS
ID : U54 MD007595
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA163227
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA188609
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA214091
Pays : United States
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