Androgen deprivation therapy is the mainstay of prostate cancer treatment, however, resistance inevitably develops, resulting in a more aggressive disease, known as castration-resistant prostate cancer (CRPC). While, enzalutamide provides a substantial survival benefit by targeting the AR, it is not curative and many patients develop resistance to therapy. Although not yet fully understood, resistance can develop through multiple mechanisms, such as AR copy number gain or the generation of splice variants such as AR-V7. circular RNAs (circRNA) are a type of non-coding RNA that have an important function in gene regulation and may play a role in drug resistance, through the regulation of miRNA circRNAs are tissue specific, stable and may represent a novel marker of drug resistance in PCa.
circRNA profiling was performed on an isogenic PCa cell line model consisting of enzalutamide sensitive and resistant subtypes using a high throughput microarray assay. Subsequently, bioinformatic analyses predicted five miRNA binding sites (miRNA Response Elements) for each circRNA and these were stratified based on known associations with PCa. Targets were validated using qPCR.
circRNAs were more often downregulated in resistant cell lines compared to sensitive lines (588 versus 278). hsa_circ_0004870 was significantly downregulated in enzalutamide resistant cells compared with control. RBM39 was determined as the parental gene, which encodes a member of the U2AF65 family of proteins. Previous studies have shown that, U2AF65 results in the expression of AR-V7, by binding to AR pre-mRNA. Expression of all genes were confirmed within our enzalutamide model.
hsa_circ_0004870 is linked to the generation of AR-V7 and may play a key role in the development of enzalutamide resistance in CRPC via a miRNA mediated mechanism.
Clinical trial identification
Legal entity responsible for the study
Trinity College Dublin
Irish Cancer Society
All authors have declared no conflicts of interest.