Abstract
The transcription factor E74-like factor 5 (ELF5) is a potent antioncogene that can prevent epithelial-mesenchymal transition (EMT) and metastasis in prostate cancer (PCa). However, little is known how it suppress the tumor growth and if it can interact with androgen receptor (AR). In this study, we find that the ELF5 is frequently expressed in AR activated PCa cells, where it binds to AR acting as a physiological partner and negatively regulates its transcriptional activity. In addition, the interaction between ELF5 and AR is androgen-dependent. Downregulation of ELF5 by shRNA increases the expression of AR-response genes and the progression of PCa. Moreover, ELF5 is a AR-dependent gene that its expression can be induced by androgen and suppressed by antiandrogen treatment. Notably, forced reduction of ELF5 in LNCaP cells facilitates the binding of AR to ARE in ELF5 gene and enabling its transcription, so that low level ELF5 can turn up its own expression by the negative feedback loop.
Highlights
Prostate cancer (PCa) is the most common cancer among men in the Western countries[1]
We found that transient expression of androgen receptor (AR) increased the androgen induction of prostate specific antigen (PSA) promoter reporter (PSA-Luc) activity about 16.5 fold compared with mock vector, and 6.5 fold compared with its neighbor group that without DHT treatment (Fig. 4E)
Identifying coregulators that are implicated in the reprogramming of AR function would give us more helpful opportunities for castration resistant prostate cancer (CRPC) detection and individually therapeutic intervention
Summary
Prostate cancer (PCa) is the most common cancer among men in the Western countries[1]. The main subset of mechanisms of resistance to ADT include overexpression of AR gene, independently active AR spliced variants, dysregulation of its suppressor, and the increased androgen synthesis[3]. AR regulates its target gene expression through interaction with coregulators, including activators and repressors[10,11,12]. E74-like factor 5 (ELF5) is a transcriptional factor and regulates diverse cellular biology including later stages of terminal differentiation of keratinocytes[14], trophoblast differentiation[15] and epithelial-mesenchymal transition (EMT) in tumor cells[16,17,18]. Our data show that ELF5 emerged as an androgen-regulated tumor-suppressor gene in PCa. we reveal a resistance mechanism to enzalutamide that caused by loss of ELF5, which results from the remission of AR inhibition by ELF5. The findings of low expression of ELF5 in mCRPC confirm that loss of ELF5 is supposed to be one of the mechanisms of CRPC
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