Abstract
Androgens and androgen receptors are vital factors involved in prostate cancer progression, and androgen ablation therapies are commonly employed to treat advanced prostate cancer. Previously, FUsed in Sarcoma (FUS) was identified as an AR-interacting protein that enhances AR transcriptional activity. In the present study, we attempted to identify miRNAs that might target both FUS and AR to inhibit FUS and AR expression. Based on TCGA data and the online tools UALCAN, Kaplan Meier-plotter (KMplot), LncTar and miRWalk prediction, miR-133a-5p was selected. MiR-133a-5p expression was significantly downregulated in prostate cancer, and low miR-133a-5p expression was correlated with low survival probability. As predicted by LncTar and miRWalk, miR-133a-5p could bind to the 3'UTR of FUS and AR to inhibit their expression. MiR-133a-5p overexpression significantly suppressed the cell viability of the AR-positive prostate cancer cell lines VCaP and LNCaP, inhibited the expression of FUS, AR, as well as AR downstream targets IGF1R and EGFR. More importantly, miR-133a inhibition increased cancer cell proliferation as well as the expression of AR and AR downstream factors, while FUS knockdown exerted an opposite effect; the effect of miR-133a on cancer cell proliferation and AR could be significantly reversed by FUS knockdown. Moreover, IGF1R and EGFR knockdown reversed the effect of the miR-133a-5p inhibition. In summary, miR-133a-5p inhibits AR-positive prostate cancer cell proliferation by targeting FUS/AR, thus improving the resistance of prostate cancer to androgen ablation therapies, which requires further in vivo validation. We provided a novel miRNA regulation mechanism for proliferation regulation in AR-positive prostate cancer cells.