Abstract
The androgen receptor (AR) has a central role in development and maintenance of the male reproductive system and in the etiology of prostate cancer. The transcription factor Pax6 has recently been reported to act as a repressor of AR and to be hypermethylated in prostate cancer cells. SPBP is a transcriptional regulator that previously has been shown to enhance the activity of Pax6. In this study we have identified SPBP to act as a transcriptional coactivator of AR. We also show that Pax6 inhibits SPBP-mediated enhancement of AR activity on the AR target gene probasin promoter, a repression that was partly reversed by increased expression of SPBP. Enhanced expression of Pax6 reduced the amount of SPBP associated with the probasin promoter when assayed by ChIP in HeLa cells. We mapped the interaction between both AR and SPBP, and AR and Pax6 to the DNA-binding domains of the involved proteins. Further binding studies revealed that Pax6 and SPBP compete for binding to AR. These results suggest that Pax6 represses AR activity by displacing and/or inhibiting recruitment of coactivators to AR target promoters. Understanding the mechanism for inhibition of AR coactivators can give rise to molecular targeted drugs for treatment of prostate cancer.
Highlights
The androgen receptor (AR) and androgens have a central role in development and maintenance of the male reproductive system and in the etiology of prostate cancer [1,2], the most commonly diagnosed invasive cancer in men in the USA and other western countries [3]
Recent reports show Pax6 to be a repressor of AR activity [29], and the PAX6 gene to be hypermethylated in prostate cancer cells [34]. p285PB-Luc contains a fragment of the AR targeted rat probasin promoter upstream of the luciferase gene [31]
These results encouraged us to investigate whether Pax6 and Stromelysin-1 PDGF-responsive element Binding Protein (SPBP) together would have any impact on AR activity
Summary
The androgen receptor (AR) and androgens have a central role in development and maintenance of the male reproductive system and in the etiology of prostate cancer [1,2], the most commonly diagnosed invasive cancer in men in the USA and other western countries [3]. Stromelysin-1 PDGF-responsive element Binding Protein (SPBP) is a 220 kDa nuclear protein displaying structural and functional properties of a transcriptional regulator It contains an N-terminal TAD, three nuclear localization signals (NLS), a DBD containing an AT-hook motif, and a C-terminal extended plant homeodomain (ePHD) [8]. We mapped the interaction between AR and the AR repressor and developmental transcription factor Pax to involve their respective DBDs. Importantly, Pax inhibited the SPBPmediated enhancement of AR activity on the AR targeted probasin promoter. Pax inhibited the SPBPmediated enhancement of AR activity on the AR targeted probasin promoter This repression was partly reversed by increased expression of SPBP. In vitro binding studies revealed that Pax and SPBP compete for binding to the AR(DBD) This suggests that Pax represses AR activity by displacing and/or inhibiting recruitment of coactivators to AR target promoters
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