ELF3 is a repressor of androgen receptor action in prostate cancer cells

Abstract

The androgen receptor (AR) plays a critical role in the development and progression of prostate cancer (PC) and is a major therapeutic target in this disease. The transcriptional activity of AR is modulated by the co-regulators with which it interacts and consequently deregulation of cofactor expression and/or activity impacts the expression of genes whose products can play a role in PC pathogenesis. Here we report that ELF3, a member of the ETS family of transcription factors, is a repressor of AR transcriptional activity. Exogenous expression of ELF3 represses AR transcriptional activity when assessed using reporter-based transfection assays or when evaluated on endogenous AR target genes. Conversely, ELF3 knockdown increases the AR transcriptional activity. Biochemical dissection of this activity indicates that it results from the physical interaction between ELF3 and AR and that this interaction inhibits the recruitment of AR to specific androgen response elements within target gene promoters. Significantly, we observed that depletion of ELF3 expression in LNCaP cells promotes cell migration while increased ELF3 expression severely inhibits tumor growth in vitro and in a mouse xenograft model. Taken together, these results suggest that modulation of ELF3 expression and/or AR/ELF3 interaction may have utility in the treatment of PC.

319 Using gene expression from urine sediment to diagnose prostate cancer: Development of a new multiplex mRNA urine test and validation of current biomarkers

“…Alterations in expression of histone HIST1H2BG were associated with biochemical recurrence in PCa patients after radical prostatectomy [26]. The transcription factor ELF3 (E74-like factor 3), that acts as a negative modulator of androgen receptor transcriptional activity, was found underexpressed in PCa [27], according to our results. On the other hand, SPP1 (secreted phosphoprotein 1) encodes the protein osteopontin (OPN).…”

Moonlighting proteins in cancer

“…In terms of oncogenic mechanism, ESE-1 is a target of oncogenic kinase, PAK1 and phosphorylated ESE-1 increase stabilize and cause transformation of breast cancer cells [69]. On the contrary, increased expression of ESE-1 inhibited tumorigenesis in prostate cancer cells [99] and resulted in reduced tumorigenicity through the TGF-β-mediated pathway [14]. In terms of two distinct ESE-1 function, Prescott et al ., reported that cytosolic ESE-1 leads to transformation of breast cancer through SAR domain-mediated pathway, whereas nuclear ESE-1 increase apoptosis through transcriptional-mediated pathway [90].…”

ESE‑1 suppresses the growth, invasion and migration of human NSCLC cells and tumor formation in�vivo

“…ESE-1 expression also led to two conflicting results in prostate cancer cells. For example, ESE-1 expression mediated transforming phenotypes (13) while ESE-1 repressed androgen-receptor action and growth/migration of prostate tumors (14). These contradictory results strongly support a dichotomous effect of ESE-1 depending on the cellular context.…”