Koushyar, Sarah, Economides, G, Zaat, Sharlene, Jiang, Wen ![]() |
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Abstract
Prohibitin (PHB) is a tumour suppressor molecule with pleiotropic activities across several cellular compartments including mitochondria, cell membrane and the nucleus. PHB and the steroid-activated androgen receptor (AR) have an interplay where AR downregulates PHB, and PHB represses AR. Additionally, their cellular locations and chromatin interactions are in dynamic opposition. We investigated the mechanisms of cell cycle inhibition by PHB and how this is modulated by AR in prostate cancer. Using a prostate cancer cell line overexpressing PHB, we analysed the gene expression changes associated with PHB-mediated cell cycle arrest. Over 1000 gene expression changes were found to be significant and gene ontology analysis confirmed PHB-mediated repression of genes essential for DNA replication and synthesis, for example, MCMs and TK1, via an E2F1 regulated pathway— agreeing with its G1/S cell cycle arrest activity. PHB is known to inhibit E2F1-mediated transcription, and the PHB:E2F1 interaction was seen in LNCaP nuclear extracts, which was then reduced by androgen treatment. Upon two-dimensional western blot analysis, the PHB protein itself showed androgen-mediated charge differentiation (only in AR-positive cells), indicating a potential dephosphorylation event. Kinexus phosphoprotein array analysis indicated that Src kinase was the main interacting intracellular signalling hub in androgen-treated LNCaP cells, and that Src inhibition could reduce this AR-mediated charge differentiation. PHB charge change may be associated with rapid dissociation from chromatin and E2F1, allowing the cell cycle to proceed. The AR and androgens may deactivate the repressive functions of PHB upon E2F1 leading to cell cycle progression, and indicates a role for AR in DNA replication licensing.
Item Type: | Article |
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Date Type: | Published Online |
Status: | Published |
Schools: | Medicine |
Subjects: | Q Science > Q Science (General) R Medicine > R Medicine (General) |
Publisher: | Nature Publishing Group |
ISSN: | 2157-9024 |
Funders: | The Cardiff University - Peking University Cancer Institute |
Date of First Compliant Deposit: | 15 May 2017 |
Date of Acceptance: | 27 March 2017 |
Last Modified: | 03 May 2023 22:47 |
URI: | https://orca.cardiff.ac.uk/id/eprint/100583 |
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