Abstract
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.
Highlights
The breakthrough discovery of fusion genes formed by recurrent chromosomal rearrangements in prostate cancer in past decade contributes significantly to our current conceptual understanding on the significance of androgen signaling in prostate carcinogenesis [1], and makes considerable impact on the early diagnosis, prognosis, and potential therapeutic management of this cancer [2, 3].These recurrent fusion genes prevalent in prostate cancer are formed by fusion of the promoter and 5′-untranslated region (UTR, exon 1 or 2) of the androgen-regulated prostate-specific transmembrane protease serine 2 gene (TMPRSS2) with the translated regions of members of erythroblastosis virus E26 transforming sequence (ETS) family of transcription factors, ERG and ETV1 [1]
In order to elucidate whether increased expressions of ERRα and ERG expressed by the T:E fusion gene would play a role in the advanced progression of prostate cancer, we analyzed the expression profiles of ERRα and ERG in clinical prostate tumor tissues and their association with the tumor grade and metastasis of patients using the cancer genomic datasets from the Cancer Genome Atlas
These results showed that up-regulation of both ERRα and ERG was positively correlated with the Gleason scores and metastasis in prostate cancer tissues
Summary
The breakthrough discovery of fusion genes formed by recurrent chromosomal rearrangements in prostate cancer in past decade contributes significantly to our current conceptual understanding on the significance of androgen signaling in prostate carcinogenesis [1], and makes considerable impact on the early diagnosis, prognosis, and potential therapeutic management of this cancer [2, 3].These recurrent fusion genes prevalent in prostate cancer are formed by fusion of the promoter and 5′-untranslated region (UTR, exon 1 or 2) of the androgen-regulated prostate-specific transmembrane protease serine 2 gene (TMPRSS2) with the translated regions of members of erythroblastosis virus E26 transforming sequence (ETS) family of transcription factors, ERG and ETV1 [1]. In order to demonstrate whether the T:E fusion could be regulated by ERRα, we examined the effects of suppression of ERRα activity or its overexpression in two prostate cancer cell lines, VCaP and NCI-H660, both harbor the T:E fusion gene and express T:E transcripts and ERG protein [1, 29].
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