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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Control of androgen receptor signaling in prostate cancer by the cochaperone small glutamine-rich tetratricopeptide repeat containing protein α
Cancer Research, Volume 67, No. 20, Year 2007
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Description
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 α (αSGT), interacts with the hinge region of the human AR in yeast and mammalian cells. Overexpression and RNA interference revealed that αSGT 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 αSGT on AR function are mediated by interaction in the cytoplasm and are distinct from the receptors response to classic coregulators. Quantitative immunohistochemical analysis of βSGT 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/βSGT 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 αSGTas 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. ©2007 American Association for Cancer Research.
Authors & Co-Authors
Scher, Howard I.
United States, New York
Memorial Sloan-kettering Cancer Center
United States, New York
Weill Cornell Medicine
Coetzee, Gerhard A.
United States, Los Angeles
University of Southern California
Tilley, Wayne D.
Australia, Adelaide
Adelaide Medical School
Statistics
Citations: 79
Authors: 3
Affiliations: 5
Identifiers
Doi:
10.1158/0008-5472.CAN-07-1646
ISSN:
00085472
Research Areas
Cancer
Study Design
Cohort Study
Study Approach
Quantitative