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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Disruption of androgen receptor-cofactor interactions by the RNA-binding protein FUS/TLS alters androgen signalling
G N Brooke1, D A Leach2, R L Culley2
1School of Life Sciences, University of Essex, Wivenhoe Park, Colchester, ESSEX, UK. gbrooke@essex.ac.uk.
Abstract:
Prostate cancer is dependent upon the androgen receptor (AR), the activity of which is modified by cofactors that either enhance or repress its activity, often in a context-dependent manner. FUS/TLS is a multifunctional protein known to be important in multiple cancer types; in prostate cancer, we previously showed that FUS has a potential tumour suppressor role. Here, transcriptomic analysis of the LNCaP prostate cancer cell line shows a significant overlap in genes regulated by FUS and the androgen receptor. We demonstrate that FUS can regulate androgen receptor activity, in either direction, but predominantly represses androgen signalling. Reporter assays and domain-specific analyses of FUS identified mechanisms by which FUS modifies androgen receptor activity. FUS interacts with the androgen receptor and other cofactors to repress transcription; ChIP assays suggest that repression occurs via disassembly of the transcriptional complex. Quantitative proteomics and RNA-Seq were used to investigate FUS expression in patient samples across prostate cancer stages. FUS was found to be down-regulated in primary tumours, but up-regulated in advanced aggressive stages. These findings suggest that in early prostate cancer, FUS represses AR activity and tumour progression, leading to its down-regulation. In contrast, increased FUS expression in advanced disease appears to be linked to a loss of AR regulatory control.
Insights
FUS protein represses androgen receptor (AR) activity in early prostate cancer, acting as a tumor suppressor. Its expression changes with disease stage, suggesting a complex role in prostate cancer progression.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Prostate cancer progression is linked to androgen receptor (AR) activity, modulated by cofactors.
- FUS/TLS is a multifunctional protein with a previously suggested tumor suppressor role in prostate cancer.
Purpose of the Study:
- To investigate the role of FUS in regulating AR activity in prostate cancer.
- To understand the expression patterns of FUS in different stages of prostate cancer.
Main Methods:
- Transcriptomic analysis (RNA-Seq) of LNCaP cells.
- Reporter assays and domain-specific analyses of FUS.
- Chromatin immunoprecipitation (ChIP) assays.
- Quantitative proteomics.
Main Results:
- FUS significantly overlaps with AR-regulated genes and predominantly represses AR signaling.
- FUS interacts with AR and cofactors, potentially disrupting transcriptional complex assembly.
- FUS is down-regulated in primary tumors but up-regulated in advanced, aggressive prostate cancer stages.
Conclusions:
- FUS acts as a repressor of AR activity and tumor progression in early prostate cancer, explaining its down-regulation.
- Altered FUS expression in advanced disease may indicate a loss of AR regulatory control, contributing to aggressive tumor behavior.
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