Nuclear receptor ERRα and transcription factor ERG form a reciprocal loop in the regulation of TMPRSS2:ERG fusion gene in prostate cancer
| Autor: | Zhenyu Xu, Xian Zhang, Yuliang Wang, Shan Yu, Chang Zou, Zhu Wang, Zhan Gang Xiao, Dinglan Wu, Franky L. Chan |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Cancer Research Oncogene Proteins Fusion Mice SCID Biology TMPRSS2 Article Metastasis Fusion gene 03 medical and health sciences Prostate cancer Mice 0302 clinical medicine Transcriptional Regulator ERG Cell Line Tumor Genetics medicine Animals Humans Molecular Biology Transcription factor Regulation of gene expression Serine Endopeptidases Prostate medicine.disease Androgen receptor Gene Expression Regulation Neoplastic Prostatic Neoplasms Castration-Resistant 030104 developmental biology Receptors Estrogen Receptors Androgen 030220 oncology & carcinogenesis Cancer research Androgens Trans-Activators Erg Signal Transduction |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 0950-9232 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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