Androgenic control of transforming growth factor-beta signaling in prostate epithelial cells through transcriptional suppression of transforming growth factor-beta receptor II.

The androgen receptor cross-talks with transforming growth factor-beta (TGF-beta) through mechanisms that remain poorly understood. Here we provide strong evidence that 5alpha-dihydrotestosterone (DHT) intercepts the ability of prostate epithelial cells to undergo TGF-beta-induced apoptosis, and present a new model for this androgenic effect. We report that DHT decreases the level of TGF-beta receptor II (TbetaRII) through a transcriptional mechanism, leading to suppression of the ability of TGF-beta to down-regulate expression of Bcl-xL and cyclin Ds, activate caspase-3, and induce apoptosis. Promoter analysis, DNA pulldown, and electrophoretic mobility shift assays support that transcriptional down-regulation of TbetaRII by DHT occurs through Sp1/Sp3 response elements, with the binding of Sp1 to the TbetaRII promoter being suppressed by DHT, largely driven by loss of Sp1 protein and/or activity. These results provide fresh insight on the mechanism of growth control by androgens and the progression of prostate cancer to androgen independence. [Cancer Res 2008;68(19):8173-82].