Orphan nuclear receptor estrogen-related receptor-beta suppresses in vitro and in vivo growth of prostate cancer cells via p21(WAF1/CIP1) induction and as a potential therapeutic target in prostate cancer
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AbstractRecent 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.
All Author(s) ListYu S, Wong YC, Wang XH, Ling MT, Ng CF, Chen S, Chan FL
Journal nameOncogene
Volume Number27
Issue Number23
Pages3313 - 3328
LanguagesEnglish-United Kingdom
KeywordsERR beta; estrogen receptor-related; estrogen-related receptor; orphan nuclear receptor; prostate cancer; receptor; tumor suppression
Web of Science Subject CategoriesBiochemistry & Molecular Biology; BIOCHEMISTRY & MOLECULAR BIOLOGY; Cell Biology; CELL BIOLOGY; Genetics & Heredity; GENETICS & HEREDITY; Oncology; ONCOLOGY

Last updated on 2020-03-06 at 00:49