Yu S, Wong Y C, Wang X H, Ling M T, Ng C F, Chen S, Chan F L
Department of Anatomy, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
Oncogene. 2008 May 22;27(23):3313-28. doi: 10.1038/sj.onc.1210986. Epub 2007 Dec 10.
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 ERRbeta in prostate cancer cell growth regulation in an androgen-sensitive and androgen-insensitive prostate cancer cell lines. ERRbeta was expressed in normal human prostates, but exhibited a reduced expression in prostate cancer lesions. Stable ERRbeta 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 ERRbeta could directly transactivate p21 gene promoter, which could be further enhanced by peroxisome proliferator-activated receptor-gamma coactivator-1alpha. Truncation analysis showed that ERRbeta-mediated p21 transactivation and prostate cancer cell growth inhibition required intact DNA-binding domain and AF2 domains in ERRbeta. Interestingly, ERRbeta displayed a cell cycle associated downregulated expression pattern in ERRbeta-transduced and non-transduced cells. Finally, we showed that ERRbeta-mediated growth inhibition could be potentiated by an ERRbeta/gamma agonist DY131. Knockdown of ERRbeta by RNA interference could reduce the DY131-induced growth inhibition in prostate cancer cells. Taken together, our findings indicate that ERRbeta performs a tumor suppressing function in prostate cancer cells, and targeting ERRbeta could be a potential therapeutic strategy for prostate cancer.
最近的研究表明，雌激素相关受体（ERRs）参与类似的雌激素受体（ER）调节途径，并在能量和脂质代谢中发挥作用。在此，我们分析了ERRβ在雄激素敏感和雄激素不敏感前列腺癌细胞系中对前列腺癌细胞生长调节的功能作用。ERRβ在正常人类前列腺中表达，但在前列腺癌病变中表达降低。稳定表达ERRβ可显著抑制LNCaP和DU145细胞的增殖和致瘤性，同时伴有S期抑制和p21表达增加。报告基因和染色质免疫沉淀分析表明，ERRβ可直接反式激活p21基因启动子，而过氧化物酶体增殖物激活受体γ共激活因子-1α可进一步增强这种激活作用。截短分析表明，ERRβ介导的p21反式激活和前列腺癌细胞生长抑制需要ERRβ完整的DNA结合结构域和AF2结构域。有趣的是，在转导ERRβ和未转导ERRβ的细胞中，ERRβ均呈现与细胞周期相关的下调表达模式。最后，我们发现ERRβ/γ激动剂DY131可增强ERRβ介导的生长抑制作用。通过RNA干扰敲低ERRβ可降低DY131诱导的前列腺癌细胞生长抑制作用。综上所述，我们的研究结果表明，ERRβ在前列腺癌细胞中发挥肿瘤抑制功能，靶向ERRβ可能是前列腺癌的一种潜在治疗策略。
