1. ¹Department of Anatomy, The Chinese University of Hong Kong, Shatin, Hong Kong, China
2. ²Department of Anatomy, The University of Hong Kong, Hong Kong, China
3. ³Department of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong, China
4. ⁴Department of Surgical Research, The Beckman Research Institute of the City of Hope, Duarte, CA, USA

Correspondence: Dr FL Chan, Department of Anatomy, The Chinese University of Hong Kong (CUHK), Basic Medical Sciences Building, Shatin, New Territories, Hong Kong, China. E-mail: franky-chan@cuhk.edu.hk

Received 31 October 2007; Accepted 14 November 2007; Published online 10 December 2007.

Abstract

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 in prostate cancer cell growth regulation in an androgen-sensitive and androgen-insensitive prostate cancer cell lines. ERR was expressed in normal human prostates, but exhibited a reduced expression in prostate cancer lesions. Stable ERR 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 ERR could directly transactivate p21 gene promoter, which could be further enhanced by peroxisome proliferator-activated receptor- coactivator-1. Truncation analysis showed that ERR-mediated p21 transactivation and prostate cancer cell growth inhibition required intact DNA-binding domain and AF2 domains in ERR. Interestingly, ERR displayed a cell cycle associated downregulated expression pattern in ERR-transduced and non-transduced cells. Finally, we showed that ERR-mediated growth inhibition could be potentiated by an ERR/ agonist DY131. Knockdown of ERR by RNA interference could reduce the DY131-induced growth inhibition in prostate cancer cells. Taken together, our findings indicate that ERR performs a tumor suppressing function in prostate cancer cells, and targeting ERR could be a potential therapeutic strategy for prostate cancer.