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Control of Androgen Receptor Signaling in Prostate Cancer by the Cochaperone Small Glutamine–Rich Tetratricopeptide Repeat Containing Protein

¹ Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, The University of Adelaide/Hanson Institute, Adelaide, South Australia, Australia; ² Centre for Molecular Biotechnology, School of Life Sciences, Queensland University of Technology, Brisbane, Queensland, Australia; ³ Department of Preventive Medicine, USC/Norris Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California; and ⁴ Genitourinary Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center, Department of Medicine, Joan and Sanford I. Weill College of Medicine, New York, New York

Requests for reprints: Grant Buchanan and Wayne D. Tilley, Department of Medicine, Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, The University of Adelaide/Hanson Institute, P.O. Box 14, Rundle Mall, Adelaide, South Australia 5000, Australia. Phone: 61-88222-3261; Fax: 61-88222-3217; E-mail: grant.buchanan{at}imvs.sa.gov.au and wayne.tilley{at}imvs.sa.gov.au.

Although the androgen receptor (AR) is accepted as the major determinant of prostate cancer cell survival throughout disease progression, it is currently unclear how the receptor sustains genomic signaling under conditions of systemic androgen ablation. Here, we show that the evolutionarily conserved Hsp70/Hsp90 cochaperone, small glutamine–rich tetratricopeptide repeat containing protein (SGT), interacts with the hinge region of the human AR in yeast and mammalian cells. Overexpression and RNA interference revealed that SGT acts to (a) promote cytoplasmic compartmentalization of the AR, thereby silencing the receptors basal/ligand-independent transcriptional activity, (b) regulate the sensitivity of receptor signaling by androgens, and (c) limit the capacity of noncanonical ligands to induce AR agonist activity. Immunofluorescence, coactivator, and chromatin immunoprecipitation analyses strongly suggest that these effects of SGT on AR function are mediated by interaction in the cytoplasm and are distinct from the receptors response to classic coregulators. Quantitative immunohistochemical analysis of SGT and AR levels in a cohort of 32 primary and 64 metastatic human prostate cancers revealed dysregulation in the level of both proteins during disease progression. The significantly higher AR/SGT ratio in metastatic samples is consistent with the sensitization of prostate tumor cells to androgen signaling with disease progression, particularly in a low-hormone environment. These findings implicate SGT as a molecular rheostat of in vivo signaling competence by the AR, and provide new insight into the determinants of androgen sensitivity during prostate cancer progression. [Cancer Res 2007;67(20):10087–96]

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