αSGT: A critical determinant of androgen receptor function in prostate cancer.

Proc Amer Assoc Cancer Res, Volume 47, 2006 5346 The maturation, activation and function of nuclear receptors depend upon their chaperone mediated folding. Here we report that a novel co-chaperone, small glutamine-rich tetratricopeptide repeat containing protein (αSGT), interacts with the androgen receptor (AR) to control both its subcellular localization and sensitivity of ligand-dependent activation in prostate cancer cells. Overexpression of αSGT sequesters AR in the cytoplasm in the absence of 5α-dihydrotestosterone (DHT), reducing basal cross-talk activation by more than 90%, as well as inhibiting the sensitivity of ligand-dependent nuclear translocation and activation. In contrast knock-down of αSGT increased AR sensitivity to DHT. In clinical prostate cancer samples, quantitative immunohistochemical analysis of AR and αSGT immunoreactivity revealed that a decrease in the ratio of AR:αSGT was associated with an increase in the relative amount of cytoplasmic compared to nuclear AR. Moreover, there was a net increase in the ratio of AR:αSGT in metastatic prostate cancer samples [2.08(+0.36), n=64] compared to primary tumors [0.99(+0.12), n=32; p=0.003], which may in part explain the increase in sensitivity of AR signaling associated with the failure of androgen ablation therapies and the development of a castrate-resistant phenotype. We propose that αSGT is a critical AR co-chaperone regulating androgen signaling, and that perturbation of the AR:αSGT ratio alters the capacity of ligand to activate the AR and stimulate the growth of prostate cancer cells.