Ubiquitin-mediated regulation of androgen receptor function: a potential therapeutic target in prostate cancer
Lead Research Organisation:
Newcastle University
Department Name: Northern Institute for Cancer Research
Abstract
More than 10,000 men die annually in the UK from prostate cancer. The standard therapy for prostate cancer aims to block the androgen receptor signalling pathway by removing its activating hormone, androgen from the circulation and/or blocking androgen action. However, most cancers become resistant to treatment and become refractory to hormone manipulation. The outlook for these patients is poor.
A detailed functional analysis of the proteins that contribute towards signalling through the androgen receptor pathway should identify alternative, novel targets for treatment of this disease.
In this project we will focus on studying the enzymes that modify the function of proteins by directly attaching or removing a small protein called ubiquitin. Addition of ubiquitin, termed ubiquitination, or removal of ubiquitin from proteins, termed deubiquitination, are important events in regulating many of the functions of the androgen receptor.
Activation of the androgen receptor is critical to all the stages of prostate cancer, including later stages of the disease when standard treatments are ineffective. We aim to identify those proteins implicated in androgen receptor ubiquitination and deubiquitination and further determine the importance of these proteins in androgen receptor action. Our ultimate hope is that we can disrupt the enzymatic action of these proteins using small molecule chemical inhibitors. In this way we may be able to provide alternative treatments for those prostate cancer patients who no longer respond to standard treatments.
Consistent with our research Institute?s policy we will fully engage the wider public with our research findings through press communications, organised open days, school visits and attendance at charity events.
A detailed functional analysis of the proteins that contribute towards signalling through the androgen receptor pathway should identify alternative, novel targets for treatment of this disease.
In this project we will focus on studying the enzymes that modify the function of proteins by directly attaching or removing a small protein called ubiquitin. Addition of ubiquitin, termed ubiquitination, or removal of ubiquitin from proteins, termed deubiquitination, are important events in regulating many of the functions of the androgen receptor.
Activation of the androgen receptor is critical to all the stages of prostate cancer, including later stages of the disease when standard treatments are ineffective. We aim to identify those proteins implicated in androgen receptor ubiquitination and deubiquitination and further determine the importance of these proteins in androgen receptor action. Our ultimate hope is that we can disrupt the enzymatic action of these proteins using small molecule chemical inhibitors. In this way we may be able to provide alternative treatments for those prostate cancer patients who no longer respond to standard treatments.
Consistent with our research Institute?s policy we will fully engage the wider public with our research findings through press communications, organised open days, school visits and attendance at charity events.
Technical Summary
Androgen ablation is widely used in prostate cancer (CaP) therapy. However, most tumours become resistant to treatment but still retain a functional androgen receptor (AR) signalling pathway.
Proteasomal turnover and transcriptional activity of the AR are subject to regulatory control by ubiquitination. Characterising the proteins that regulate ubiquitination of the AR may provide alternative targets for treatment of advanced CaP.
This study will determine the regulatory influence of ubiquitination on transcriptional activity and proteasomal degradation of the AR and further investigate the potential of using small molecule inhibitors to disrupt ubiquitin-mediated AR signalling in CaP. The aim is to identify novel protein within the AR protein transcriptional complex as alternative targets for therapeutic intervention in CaP.
This project will
(1) Investigate the degradation of wild type and mutant AR in CaP cell lines in response to ligand modulation and proteasomal inhibitors
(2) Apply small molecule inhibitors that modulate AR phosphorylation or interfere with AR chaperone binding to investigate AR degradation and function
(3) Determine the sites of ubiquitination of the AR both in vitro and in vivo
(4) Identify deubiquitinating enzymes linked to AR transcriptional activity
(5) Evaluate protein expression and genetic alterations of selected gene products that modulate AR ubiquitination in clinical material to determine their relevance to the initiation and progression of CaP
Proteasomal turnover and transcriptional activity of the AR are subject to regulatory control by ubiquitination. Characterising the proteins that regulate ubiquitination of the AR may provide alternative targets for treatment of advanced CaP.
This study will determine the regulatory influence of ubiquitination on transcriptional activity and proteasomal degradation of the AR and further investigate the potential of using small molecule inhibitors to disrupt ubiquitin-mediated AR signalling in CaP. The aim is to identify novel protein within the AR protein transcriptional complex as alternative targets for therapeutic intervention in CaP.
This project will
(1) Investigate the degradation of wild type and mutant AR in CaP cell lines in response to ligand modulation and proteasomal inhibitors
(2) Apply small molecule inhibitors that modulate AR phosphorylation or interfere with AR chaperone binding to investigate AR degradation and function
(3) Determine the sites of ubiquitination of the AR both in vitro and in vivo
(4) Identify deubiquitinating enzymes linked to AR transcriptional activity
(5) Evaluate protein expression and genetic alterations of selected gene products that modulate AR ubiquitination in clinical material to determine their relevance to the initiation and progression of CaP
Organisations
People |
ORCID iD |
| Craig Robson (Principal Investigator) |