Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

Mechanisms involved in the development of androgen independent prostate: Androgen receptor activation leads to a dissociation of E2F1:PHB in prostate cancer

Koushyar, Sarah 2017. Mechanisms involved in the development of androgen independent prostate: Androgen receptor activation leads to a dissociation of E2F1:PHB in prostate cancer. PhD Thesis, Cardiff University.
Item availability restricted.

[thumbnail of 2017KoushyarS PhD.pdf]
PDF - Accepted Post-Print Version
Download (7MB) | Preview
[thumbnail of 2017KoushyarS _ThesesDissertation Publication Form.pdf] PDF - Supplemental Material
Restricted to Repository staff only

Download (154kB)


Prostate cancer (PC) is the most common cancer found in men in the Western world. Predominantly, the pathogenesis of PC is driven by aberrant androgen receptor (AR) signalling, resulting in heightened cell proliferation and cell survival. Current treatment options target the AR signalling cascade by androgen ablation therapy, whereby anti-androgens antagonistically bind to the AR. This prevents AR activity, thus inhibiting transcription of genes involved in cell proliferation, survival and metastasis. However, eventually androgen ablation therapy leads to relapse, as the cancer succumbs to a low androgen environment, leading to a poorer prognosis with limited treatment options, otherwise known as ‘castration resistant PC’ (CRPC). This is where new clinical interventions are urgently required. One mechanism that could allude to androgen independent PC, is the down-regulation of AR co-repressors. One such co-repressor is known as Prohibitin (PHB). PHB is ubiquitously expressed in mammalian cells and displays anti-proliferative functions. Prior to this project, it was identified that AR signalling leads to the down-regulation of PHB at both a transcript and protein level and causes PHB to dissociate from the chromatin. However, over-expression of PHB leads to the down-regulation of androgen responsive genes, and its increased association with the chromatin. Thus within PC, both the AR and PHB are in a dynamic opposition. This project identified that PHB has a repressive role on the cell cycle by holding the cell population within the G1 phase. RNA-sequencing and Q-PCR data identified that PHB had a significant repressive role on gene families involved in DNA replication and cell cycle regulation and progression. Such gene families include cyclins, E2Fs and MCMs. MCMs are gene targets of E2Fs, and therefore it was assessed if PHB had an effect on the promoter activity of two MCM genes; MCM5&6. Interestingly, with PHB over-expression, repression of both MCM5&6 promoter activity was seen. It was then identified that PHB physically interacts with E2F1 in androgen responsive PC cells. However this interaction was reduced upon androgen stimulation of the AR. This led to the preliminary mechanism that PHB can bind to E2F1, potentially preventing E2F from binding to MCM promoter regions, leading to an inhibition of the cell cycle in PC cells. Moreover, it was identified that androgen stimulation led to a likely dephosphorylation event happening to the PHB protein that could explain how PHB dissociates from the chromatin and E2F1. Signalling pathways that could lead to the non-genomic activation of the AR was narrowed down to the Src-pathway highlighted by a Kinexus™ protein array. Interestingly, inhibiting the Src-pathway stops PHB’s likely dephosphorylation event. Accumulating previous data and data collected throughout this thesis, PHB up-regulation leads to cell cycle arrest through a direct interact of a key cell cycle regulator; E2F1. Moreover, PHB was found to have an inhibitory effect on both the migration and adhesion of PC cells, potentially through the down-regulation of wnt genes. Thus potentially, PHB up-regulation can inhibit the migratory potential of PC cells, stopping the progression of the disease.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 24 October 2017
Last Modified: 10 Nov 2021 02:10

Actions (repository staff only)

Edit Item Edit Item


Downloads per month over past year

View more statistics