Androgens and the androgen receptor (AR) act in cells by modulating gene expression. Through gene microarray studies, we have identified three novel androgen-regulated genes: soluble guanylyl cyclase subunit al (sGCα1), Ets Variant Gene 1 (ETV1), and multi-drug resistance associated protein 4. Our data demonstrate that the mRNA and protein expressions of all three genes are up-regulated in response to androgens in androgen-dependent LNCaP cells, but not in normal prostate cells. The promoters of sGCαl and ETV1 are induced by androgens and bind to AR in the context of chromatin. sGCαl and ETV1 proteins are expressed in androgen-independent LNCaP cells unresponsive to androgen. All three genes are over-expressed in prostate cancer. Disruption of sGCαl, ETV1, or MRP4 expression in prostate cancer cells results in reduced cell growth, decreased invasion capacity, or increased sensitivity to chemotherapeutic drugs, respectively, suggesting important roles for AR-regulating gene expression in multiple stages of prostate cancer.

Our previous studies suggest that the proto-oncoprotein c-Jun is an AR coactivator that stimulates AR transactivation by mediating receptor dimerization and subsequent DNA binding. We show here that c-Jun coactivation function leads to increased prostate cancer proliferation. c-Jun also has stimulatory activity on both AR transactivation of ETV1 and subsequent ETV1 transactivation of matrix metal Ioproteinase (MMP) genes, demonstrating a key co-regulatory role for c-Jun in this novel AR-ETV1 cross-talk.