The TMPRSS2:ERG (T:E) fusion gene is generally believed to be mainly regulated by the activated androgen receptor (AR) signaling in androgen-dependent prostate cancer. However, its persistent expression in castration-resistant and neuroendocrine prostate cancers implies that other transcription factors might also regulate its expression. Here, we showed that up-regulation of nuclear receptor estrogen-related receptor alpha (ERRα) was closely associated with the oncogenic transcription factor ERG expression in prostate cancer, and their increased coexpression patterns were closely associated with high Gleason scores and metastasis in patients. Both ERRα and ERG exhibited a positive expression correlation in a castration-resistant prostate cancer (CRPC) xenograft model VCaP-CRPC. We showed that ERRα could directly transactivate T:E fusion gene in both AR-positive and -negative prostate cancer cells via both ERR-binding element- and AR-binding element-dependent manners. Ectopic T:E expression under ERRα regulation could promote both in vitro invasion and in vivo metastasis capacities of AR-negative prostatic cells. Intriguingly, ERG expressed by the T:E fusion could also transactivate the ERRα (ESRRA) gene. Hereby, ERRα and ERG can synergistically regulate each other and form a reciprocal regulatory loop to promote the advanced growth of prostate cancer. Inhibition of ERRα activity by ERRα inverse agonist could suppress T:E expression in prostate cancer cells, implicating that targeting ERRα could be a potential therapeutic strategy for treating the aggressive T:E-positive prostate cancer.

中文翻译：

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核受体 ERRα 和转录因子 ERG 在前列腺癌中 TMPRSS2:ERG 融合基因的调节中形成相互环。


一般认为，在雄激素依赖性前列腺癌中，TMPRSS2:ERG (T:E)融合基因主要受激活的雄激素受体(AR)信号调节。然而，它在去势抵抗性和神经内分泌前列腺癌中的持续表达意味着其他转录因子也可能调节其表达。在这里，我们发现核受体雌激素相关受体α（ERRα）的上调与前列腺癌中致癌转录因子ERG的表达密切相关，并且它们增加的共表达模式与患者的高格里森评分和转移密切相关。 ERRα 和 ERG 在去势抵抗性前列腺癌 (CRPC) 异种移植模型 VCaP-CRPC 中均表现出正表达相关性。我们发现ERRα可以通过ERR结合元件和AR结合元件依赖性方式直接反式激活AR阳性和阴性前列腺癌细胞中的T:E融合基因。 ERRα调控下的异位T:E表达可以促进AR阴性前列腺细胞的体外侵袭和体内转移能力。有趣的是，T:E 融合表达的 ERG 也可以反式激活 ERRα (ESRRA) 基因。由此，ERRα和ERG可以相互协同调节，形成相互调节环，促进前列腺癌的晚期生长。 ERRα反向激动剂抑制ERRα活性可以抑制前列腺癌细胞中T:E的表达，这表明靶向ERRα可能是治疗侵袭性T:E阳性前列腺癌的潜在治疗策略。