Control of androgen receptor signaling in prostate cancer by the cochaperone small glutamine rich tetratricopeptide repeat containing protein alpha.
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 alpha (alphaSGT), interacts with the hinge region of the human AR in yeast and mammalian cells. Overexpression and RNA interference revealed that alphaSGT 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 alphaSGT on AR function are mediated by interaction in the cytoplasm and are distinct from the receptors response to classic coregulators. Quantitative immunohistochemical analysis of alphaSGT 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/alphaSGT 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 alphaSGT 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.
Buchanan
Grant
G
Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, The University of Adelaide/Hanson Institute, Adelaide, South Australia, Australia. grant.buchanan@imvs.sa.gov.au
Ricciardelli
Carmela
C
Harris
Jonathan M
JM
Prescott
Jennifer
J
Yu
Zoe Chiao-Li
ZC
Jia
Li
L
Butler
Lisa M
LM
Marshall
Villis R
VR
Scher
Howard I
HI
Gerald
William L
WL
Coetzee
Gerhard A
GA
Tilley
Wayne D
WD
D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D018450:Disease Progression; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D008958:Models, Molecular; D018832:Molecular Chaperones; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic
D002352:Carrier Proteins; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D011944:Receptors, Androgen; C114575:SGTA protein, human