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

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

Estrogen-related Receptor β Reduces the Subnuclear Mobility of Estrogen Receptor α and Suppresses Estrogen-dependent Cellular Function

“…A recent report suggests that ERR␤ expression results in a better prognosis in breast cancer patients with reduced BCA2 and an increased FST level by controlling these genes (61). In addition, ERR␤ exerts a carcinostatic effect through activation of the p21 tumor suppressor gene and cell cycle regulation, which are not linked to anti-estrogenic action (69,70). In fact, our proliferation assay in MRK-nu-1 triplenegative breast cancer cells indicated a growth inhibitory action of ERR␤ independent of estrogen signaling (data not shown).…”

Mitochondrial dysfunction is induced by the overexpression of UCP4 in 3T3-L1 adipocytes

“…Targeted disruption of the ERRß gene in mice resulted in severely impaired placental formation, and the embryo died at 10.5 days post-coitum (38). ERRß overexpressed prostate cancer cell lines displayed more active mitochondria at high membrane potentials and showed improved lipid metabolism (39). Recent work has established that ERRs play a role in regulating energy metabolism and mitochondrial biogenesis and function (37,40).…”

Estrogen-Related Receptors and Breast Cancer: A Mini Review

“…The inhibition of prostate cancer cell proliferation was due to cell cycle arrest as demonstrated by the induction of cyclin-dependent kinase inhibitor p21 by ERR and p21/p27 by ERR . Moreover, ERR and ERR -mediated growth inhibition could be potentiated by their specific agonist DY131 and reduced by siRNA (Yu, Wang et al 2007;Yu, Wong et al 2008). The expression of ERR and ERR in prostate cancer is in contrast to ERR in breast cancer cells, colorectal tumor, and malignant colon cells (Cavallini, Notarnicola et al 2005).…”

“…Since the over expression of ERR in breast cancer was discovered (Ariazi, Clark et al 2002;Suzuki, Miki et al 2004), additional studies have found an association between the abnormal expression of ERRs and a variety of tumors and cancers such as prostate (Cheung, Yu et al 2005;Yu, Wang et al 2007;Yu, Wong et al 2008), ovarian (Sun, Sehouli et al 2005), colon-rectal (Cavallini, Notarnicola et al 2005) and endometrium (Gao, Sun et al 2006). In neoplastic prostatic tissues, ERR and ERR show levels that are either reduced or undetectable as compared to normal prostatic epithelial cells (Cheung, Yu et al 2005).…”