The MicroRNA miR-454 and the mediator complex component MED12 are regulators of the androgen receptor pathway in prostate cancer.

Prostate cancer that is resistant to anti-androgen treatment, such as enzalutamide, represents a therapeutic challenge. To study their molecular and functional features, the enzalutamide-resistant PCa cell lines LNCaP Abl EnzR and DuCaP EnzR constitute valuable in vitro models. In this work, we explored two different strategies for reducing AR/AR-V7/c-Myc. MED12 knockdown decreased the protein expression of AR, AR-V7 and c-Myc. Similarly, we identified AR and AR-V7 as targets of miR-454-3p. Concomitantly, the transfection of synthetic miR-454-3p reduced the protein expression of AR in both EnzR cell lines and that of c-Myc and AR-V7 in the DuCaP EnzR cell line without affecting MED12. Despite these similar molecular effects, differences were observed at the cellular level, with siMED12, but not miR-454, reducing cell viability, and no additive effects upon double treatment were observed. Taken together, the results of our study suggest MED12 as a potential target for future PCa treatment in conjunction with enzalutamide resistance. Furthermore, miR-454-3p, which directly targets AR and AR-V7 and indirectly influences c-Myc protein expression, reveals new molecular mechanisms in PCa biology.