Transcriptional regulation of the TGF-β1 promoter by androgen receptor

Abstract

TGF (transforming growth factor)-β1 is a multifunctional cytokine that influences homoeostatic processes of various tissues. TGF-β1 expression is inhibited by androgens in the prostate gland, whereas its expression is enhanced by androgens in highly metastatic prostate cancer cells. Here, we examined regulation of human TGF-β1 promoter activity by androgen in prostate cancer cells. The full-length (−3363 to +110) promoter showed a high level of activity in response to androgen in PC3mm2 cells expressing AR (androgen receptor). Further deletion analysis revealed three distal and three proximal AREs (androgen-response elements) in the promoter. Gel-shift and footprint assays show that these AREs physically interact with the DNA-binding domain of AR. Chromatin immunoprecipitation assays revealed the androgen-dependent recruitment of AR to the ARE-containing regions of the TGF-β1 gene. More importantly, a negative ARE was detected in the TGF-β1 promoter. Both positive and negative AREs are functional in the androgen-regulated transcription of the TGF-β1 promoter. These findings imply that androgen signalling may positively or negatively regulate TGF-β1 expression in response to various signals or under different environmental conditions.