Androgen-targeted hsa_circ_0085121 encodes a novel protein and improves the development of prostate cancer through facilitating the activity of PI3K/Akt/mTOR pathway and enhancing AR-V7 alternative splicing

Abstract Prostate cancer (PCa) is the most prevalent type of cancer and the second leading cause of mortality in males, with a marked increase in incidence observed across the globe. In the present study, whole-transcriptome analysis was conducted to identify differentially expressed circular RNAs (DE-circRNAs). The coding abilities of the DE-circRNAs were analyses, and it was found that hsa_circ_0085121 (circRNF19A) not only exhibited overexpression in PCa cells and tumor samples, but also encoded a 490 amino acid polypeptide designated circRNF19A-490aa. The knockdown of circRNF19A was observed to notably inhibit the proliferation, invasion, migration and docetaxel resistance of PCa cells. In contrast, mutation of the IRES significantly impaired the tumor-promoting function of circRNF19A, indicating that circRNF19A-490aa is the primary form that regulates the malignant behaviors of PCa cells. Mechanistically, circRNF19A-490aa was demonstrated to interact with HSP90AA1, thereby enhancing AR activity and facilitating the activation of the Akt/mTOR and PLK1 pathways. Furthermore, circRNF19A-490aa was observed to interact with HNRNPF, facilitating the recruitment of HNRNPF to the splicing site of AR-V7 and enhancing its alternative splicing. Finally, the androgen receptor (AR) was observed to bind to the promoter region of the RNF19A gene, subsequently regulating the expression of circRNF19A and circRNF19A-490aa. These data indicate that circRNF19A plays a pivotal role in AR activation and AR-V7 generation by encoding a novel protein, circRNF19A-490aa, and targeting circRNF19A may prove an effective strategy for impeding the progression of CRPC.