Orphan nuclear receptor estrogen-related receptor-β suppresses in vitro and in vivo growth of prostate cancer cells via p21WAF1/CIP1 induction and as a potential therapeutic target in prostate cancer

Recent studies indicate that estrogen-related receptors (ERRs) are involved in similar estrogen receptor (ER) regulatory pathways and play roles in energy and lipid metabolism. Here, we analysed the functional role of ERR beta in prostate cancer cell growth regulation in an androgen-sensitive and androgen-insensitive prostate cancer cell lines. ERR beta was expressed in normal human prostates, but exhibited a reduced expression in prostate cancer lesions. Stable ERR beta expression suppressed significantly cell proliferation and tumorigenicity of LNCaP and DU145 cells, accompanied by an S-phase suppression and increased p21 expression. Reporter and chromatin immunoprecipitation assays showed that ERRb could directly transactivate p21 gene promoter, which could be further enhanced by peroxisome proliferator-activated receptor-gamma coactivator-1 alpha. Truncation analysis showed that ERR beta-mediated p21 transactivation and prostate cancer cell growth inhibition required intact DNA-binding domain and AF2 domains in ERR beta. Interestingly, ERR beta displayed a cell cycle associated downregulated expression pattern in ERR beta-transduced and non-transduced cells. Finally, we showed that ERR beta-mediated growth inhibition could be potentiated by an ERRb/gamma agonist DY131. Knockdown of ERR beta by RNA interference could reduce the DY131-induced growth inhibition in prostate cancer cells. Taken together, our findings indicate that ERR beta performs a tumor suppressing function in prostate cancer cells, and targeting ERR beta could be a potential therapeutic strategy for prostate cancer.