Increased ABCC4 Expression Induced by ERR alpha Leads to Docetaxel Resistance via Efflux of Docetaxel in Prostate Cancer

Docetaxel is a major treatment for advanced prostate cancer (PCa); however, its resistance compromises clinical effectiveness. Estrogen receptor-related receptor alpha (ERR alpha) belongs to an orphan nuclear receptor superfamily and was recently found to be closely involved in cancer. In the present study, we found that ERR alpha was involved in docetaxel resistance in PCa. Overexpression of ERR alpha conferred docetaxel resistance in PCa cell lines, and cells with ERR alpha downregulation were more sensitive to docetaxel. Among the drug resistance-related genes, ABCC4 demonstrated synchronous expression after ERR alpha manipulation in cells. Moreover, both ERR alpha and ABCC4 were overexpressed in the docetaxel-resistant cell, which could be reversed by ERR alpha knockdown. The knockdown of ERR alpha also reversed the reduced drug accumulation in the docetaxel-resistant cell. We also demonstrated for the first time that ABCC4 was a direct target of ERR alpha as determined by the CHIP and luciferase assays. Bioinformatics analysis revealed high expression of ERR alpha and ABCC4 in PCa patients, and a number of potential ERR alpha/ABCC4 targets were predicted. In conclusion, our study demonstrated a critical role for ERR alpha in docetaxel resistance by directly targeting ABCC4 and stressed the importance of ERR alpha as a potential therapeutic target for drug-resistant PCa.