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.