2. Academic Validation
  3. Circular RNAs add diversity to androgen receptor isoform repertoire in castration-resistant prostate cancer

Circular RNAs add diversity to androgen receptor isoform repertoire in castration-resistant prostate cancer

  • Oncogene. 2019 Nov;38(45):7060-7072. doi: 10.1038/s41388-019-0947-7.
Subing Cao 1,  Tianfang Ma 1,  Nathan Ungerleider 2,  Claire Roberts 2,  Margaret Kobelski 1,  Lianjin Jin 1,  Monica Concha 2,  Xia Wang 2,  Melody Baddoo 2,  Holly M Nguyen 3,  Eva Corey 3,  Ladan Fazli 4,  Elisa Ledet 5,  Rubin Zhang 5,  Jonathan L Silberstein 5,  Wensheng Zhang 6,  Kun Zhang 6,  Oliver Sartor 5,  Xuesen Dong 4,  Erik K Flemington 7,  Yan Dong 8
Affiliations

Affiliations

  • 1 Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA, USA.
  • 2 Department of Pathology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA, USA.
  • 3 Department of Urology, University of Washington, Seattle, WA, USA.
  • 4 Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
  • 5 Department of Medicine, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA, USA.
  • 6 Department of Computer Science, Bioinformatics Facility of Xavier RCMI Center of Cancer Research, Xavier University of Louisiana, New Orleans, LA, USA.
  • 7 Department of Pathology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA, USA. [email protected].
  • 8 Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, LA, USA. [email protected].
PMID: 31409897 DOI: 10.1038/s41388-019-0947-7
Abstract

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.

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