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The prohibitin-repressive interaction with E2F1 is rapidly inhibited by androgen signalling in prostate cancer cells

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Title: The prohibitin-repressive interaction with E2F1 is rapidly inhibited by androgen signalling in prostate cancer cells
Authors: Koushyar, S
Economides, G
Zaat, S
Jiang, W
Bevan, CL
Dart, DA
Item Type: Journal Article
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.
Issue Date: 15-May-2017
Date of Acceptance: 27-Mar-2017
URI: http://hdl.handle.net/10044/1/49052
DOI: https://dx.doi.org/10.1038/oncsis.2017.32
ISSN: 2157-9024
Publisher: Springer Nature
Journal / Book Title: Oncogenesis
Volume: 6
Issue: 5
Copyright Statement: © The Author(s) 2017. Oncogenesis is an open-access journal published by Nature Publishing Group . This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article ’ s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0
Sponsor/Funder: Cancer Research UK
Prostate Cancer UK
Funder's Grant Number: 12196
PG10-25
Publication Status: Published
Conference Place: United States
Article Number: e333
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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