Control of androgen receptor signaling in prostate cancer by the cochaperone small glutamine-rich tetratricopeptide repeat containing protein α

Grant Buchanan, Carmela Ricciardelli, Jonathan M. Harris, Jennifer Prescott, Zoe Chiao Li Yu, Li Jia, Lisa M. Butler, Villis R. Marshall, Howard I. Scher, William L. Gerald, Gerhard A. Coetzee, Wayne D. Tilley

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

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.

LanguageEnglish
Pages10087-10096
Number of pages10
JournalCancer Research
Volume67
Issue number20
DOIs
Publication statusPublished - 15 Oct 2007

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Buchanan, Grant ; Ricciardelli, Carmela ; Harris, Jonathan M. ; Prescott, Jennifer ; Yu, Zoe Chiao Li ; Jia, Li ; Butler, Lisa M. ; Marshall, Villis R. ; Scher, Howard I. ; Gerald, William L. ; Coetzee, Gerhard A. ; Tilley, Wayne D. / Control of androgen receptor signaling in prostate cancer by the cochaperone small glutamine-rich tetratricopeptide repeat containing protein α. In: Cancer Research. 2007 ; Vol. 67, No. 20. pp. 10087-10096.
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abstract = "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.",
author = "Grant Buchanan and Carmela Ricciardelli and Harris, {Jonathan M.} and Jennifer Prescott and Yu, {Zoe Chiao Li} and Li Jia and Butler, {Lisa M.} and Marshall, {Villis R.} and Scher, {Howard I.} and Gerald, {William L.} and Coetzee, {Gerhard A.} and Tilley, {Wayne D.}",
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Buchanan, G, Ricciardelli, C, Harris, JM, Prescott, J, Yu, ZCL, Jia, L, Butler, LM, Marshall, VR, Scher, HI, Gerald, WL, Coetzee, GA & Tilley, WD 2007, 'Control of androgen receptor signaling in prostate cancer by the cochaperone small glutamine-rich tetratricopeptide repeat containing protein α', Cancer Research, vol. 67, no. 20, pp. 10087-10096. https://doi.org/10.1158/0008-5472.CAN-07-1646

Control of androgen receptor signaling in prostate cancer by the cochaperone small glutamine-rich tetratricopeptide repeat containing protein α. / Buchanan, Grant; Ricciardelli, Carmela; Harris, Jonathan M.; Prescott, Jennifer; Yu, Zoe Chiao Li; Jia, Li; Butler, Lisa M.; Marshall, Villis R.; Scher, Howard I.; Gerald, William L.; Coetzee, Gerhard A.; Tilley, Wayne D.

In: Cancer Research, Vol. 67, No. 20, 15.10.2007, p. 10087-10096.

Research output: Contribution to journalArticle

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AU - Prescott, Jennifer

AU - Yu, Zoe Chiao Li

AU - Jia, Li

AU - Butler, Lisa M.

AU - Marshall, Villis R.

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AU - Gerald, William L.

AU - Coetzee, Gerhard A.

AU - Tilley, Wayne D.

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