PDEF, a novel prostate epithelium-specific Ets transcription factor, interacts with the androgen receptor and activates prostate-specific antigen gene expression

Prostate cancer, the most frequent solid cancer in older men, is a leading cause of cancer deaths. Although proliferation and differentiation of norma l prostate epithelia and the initial growth of prostate cancer cells are an drogen-dependent, prostate cancers ultimately become androgen-independent a nd refractory to hormone therapy. The prostate-specific antigen (PSA) gene has been widely used as a diagnostic indicator for androgen-dependent and - independent prostate cancer. Androgen-induced and prostate epithelium-speci fic PSA expression is regulated by a proximal promoter and an upstream enha ncer via several androgen receptor binding sites. However, little progress has been made in identifying androgen-independent regulatory elements invol ved in PSA gene regulation. We report the isolation of a novel, prostate ep ithelium-specific Ets transcription factor, PDEF (prostate-derived Ets fact or), that among the Ets family uniquely prefers binding to a GGAT rather th an a GGAA core. PDEF acts as an androgen-independent transcriptional activa tor of the PSA promoter. PDEF also directly interacts with the DNA binding domain of androgen receptor and enhances androgen-mediated activation of th e PSA promoter. Our results, as well. as the critical roles of other Ets fa ctors in cellular differentiation and tumorigenesis, strongly suggest that PDEF is an important regulator of prostate gland and/or prostate cancer dev elopment.