Abstract 1385: Orphan nuclear receptor estrogen-related receptor alpha (ERRα) characterized as a novel transcriptional regulator of the oncogenic fusion gene TMPRSS2:ERG in prostate cancer

Abstract

Abstract The expression of androgen-responsive TMPRSS2:ERG fusion gene, which results in aberrant expression of the oncogenic transcription factor ERG under the regulation of androgen receptor (AR), is characterized as the predominant factor responsible for the initiation and also advanced progression of prostate cancer (PCa). However, its upstream transcriptional regulation in androgen-independent PCa is still not fully understood. Recent studies show that the orphan nuclear receptor estrogen-related receptor alpha (ERRα/NR3B1) plays certain regulatory roles in the advanced progression of prostate cancer, such as its cross-talk with AR signaling. Based on this, we hypothesize that besides AR, ERRα could also regulate or target to the promoter of fusion gene TMPRSS2:ERG in prostate cancer cells. Here we showed that treatment with an ERRα-specific inverse agonist (XCT790) or knockdown of ERRα could decrease the TMPRSS2:ERG expression in AR-positive VCaP prostate cancer cells. Besides, the expression levels of TMPRSS2:ERG could be elevated by ectopic ERRα expression, with further elevation by co-expression with a genetically modified ERRα-specific coactivator PGC1α(2X9), in AR-negative NCI-H660 prostate cancer cells. By ChIP and luciferase reporter analysis, three putative ERRα transactivation DNA binding sites were identified in the promoter region of TMPRSS2:ERG fusion gene. Besides, in vitro phenotype characterization studies showed that ectopic expression of TMPRSS2:ERG, using an ERRα-responsive and TMPRSS2:ERG fusion gene promoter-driven expression plasmid in AR-negative prostatic cell lines, including PC-3 prostate cancer cells and BPH-1 immortalized prostatic epithelial cells, could promote their invasion capacity. Moreover, both ERRα and TMPRSS2:ERG showed elevated expressions in a xenograft model of castration-resistant prostate cancer cells (VCaP-CRPC). Besides, luciferase reporter assays showed that both TMPRSS2:ERG promoter and ERRα-binding element (ERRE) transcriptional activities were elevated in VCaP-CRPC cells as compared to the VCaP parental cells; and their transcriptional activities could be suppressed by XCT790 or sh-ERRα. Based on these results, we conclude that ERRα could directly transactivate the TMPRSS2:ERG fusion gene in prostate cancer and may contribute to its transactivation in AR-negative prostate cancer cells and the advanced castration-resistant prostate cancer. This study is supported by a General Research Fund from the Research Grants Council of Hong Kong (Project code: 2140629). Citation Format: Zhenyu Xu, Shan Yu, Franky Leung Chan. Orphan nuclear receptor estrogen-related receptor alpha (ERRα) characterized as a novel transcriptional regulator of the oncogenic fusion gene TMPRSS2:ERG in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1385. doi:10.1158/1538-7445.AM2014-1385