Dart, Dafydd Alwyn, Brooke, G. N., Sita-Lumsden, A., Waxman, J. and Bevan, C. L. 2012. Reducing prohibitin increases histone acetylation, and promotes androgen independence in prostate tumours by increasing androgen receptor activation by adrenal androgens. Oncogene 31 (43) , pp. 4588-4598. 10.1038/onc.2011.591 |
Abstract
Prostate cancers (PCs), initially responsive to anti-androgen therapies, often advance to a hormone-refractory ‘castrate-resistant’ PC (CRPC) stage. However, the androgen receptor (AR) pathway remains active and key for cell growth and gene expression within tumours, even in the apparent absence of hormone. Proposed mechanisms to explain progression, including AR amplification/mutation, are insufficient to completely explain CRPC and possible roles of AR cofactors such as prohibitin (PHB) are poorly understood. We investigated whether PHB loss could sensitise PC cells and tumours to adrenal gland-derived androgens, which persist even after androgen ablation, hence contribute to development of CRPC. Using a pair of PC cell lines, inducibly expressing ectopic cDNA or RNAi for PHB, responses to different androgens and hormone concentrations were studied both in vitro and in vivo. PHB was found at the promoters of several genes, both AR and non-AR-regulated, and knockdown increased histone acetylation at these promoters. Further, PHB knockdown increased the rate of AR ligand-induced chromatin binding, and binding rate and occupancy of AR upon the PSA promoter. This resulted in increased cell growth and AR activity in response to all androgens, including promoting a response to the weaker adrenal androgens previously absent at physiological concentrations. In vivo this had functional consequences such that PHB knockdown resulted in androstenedione being sufficient to promote tumour growth, under conditions mimicking those in patients undergoing androgen ablation therapy. We conclude that reduction in PHB levels is sufficient to lower the threshold of AR activity in vitro and in vivo; this may be via a general increase in histone acetylation that could potentially affect signalling by other transcription factors. PHB loss may provide a mechanism for progression to CRPC by sensitising PC cells to ‘castrate’ conditions—that is, low levels of testicular androgens in the continued presence of weak adrenal and dietary androgens.
Item Type: | Article |
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Date Type: | Publication |
Status: | Published |
Schools: | Medicine |
Subjects: | R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) |
Uncontrolled Keywords: | prohibitin; androgen receptor; prostate; androgens; castrate-resistant prostate cancer; corepressor |
Publisher: | Nature Publishing Group |
ISSN: | 0950-9232 |
Last Modified: | 08 Jan 2020 03:30 |
URI: | https://orca.cardiff.ac.uk/id/eprint/50291 |
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