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VPRBP functions downstream of the androgen receptor and OGT to restrict p53 activation in prostate cancer

View ORCID ProfileNinu Poulose, Nicholas Forsythe, Adam Polonski, Gemma Gregg, View ORCID ProfileSarah Maguire, Marc Fuchs, View ORCID ProfileSarah Minner, Guido Sauter, View ORCID ProfileSimon S. McDade, View ORCID ProfileIan G. Mills
doi: https://doi.org/10.1101/2021.02.28.433236
Ninu Poulose
1Patrick G Johnston Centre for Cancer Research, Queen’s University, Belfast, UK, BT9 7AE
2Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom, OX3 9DU
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  • For correspondence: ian.mills@nds.ox.ac.uk ninu.poulose@nds.ox.ac.uk
Nicholas Forsythe
1Patrick G Johnston Centre for Cancer Research, Queen’s University, Belfast, UK, BT9 7AE
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Adam Polonski
3University Medical Center Hamburg-Eppendorf Department of Pathology, Hamburg, Germany, 20246
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Gemma Gregg
1Patrick G Johnston Centre for Cancer Research, Queen’s University, Belfast, UK, BT9 7AE
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Sarah Maguire
1Patrick G Johnston Centre for Cancer Research, Queen’s University, Belfast, UK, BT9 7AE
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Marc Fuchs
1Patrick G Johnston Centre for Cancer Research, Queen’s University, Belfast, UK, BT9 7AE
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Sarah Minner
3University Medical Center Hamburg-Eppendorf Department of Pathology, Hamburg, Germany, 20246
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Guido Sauter
3University Medical Center Hamburg-Eppendorf Department of Pathology, Hamburg, Germany, 20246
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Simon S. McDade
1Patrick G Johnston Centre for Cancer Research, Queen’s University, Belfast, UK, BT9 7AE
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Ian G. Mills
1Patrick G Johnston Centre for Cancer Research, Queen’s University, Belfast, UK, BT9 7AE
2Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom, OX3 9DU
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  • ORCID record for Ian G. Mills
  • For correspondence: ian.mills@nds.ox.ac.uk ninu.poulose@nds.ox.ac.uk
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Abstract

A comprehensive understanding of androgen receptor (AR) signalling mechanisms during prostate carcinogenesis is instrumental in developing novel therapies. Studies have shown glycosylation as a key androgen regulated process and that O-GlcNAc transferase (OGT), the enzyme that catalyses the covalent addition of UDP-N-acetylglucosamine (UDP-GlcNAc) to serine and threonine residues of proteins, is often up-regulated in prostate cancer (PCa) with its expression correlated with high Gleason score. In this study we have identified an AR and OGT co-regulated factor, VPRBP also known as DCAF1. We show that VPRBP is regulated by the AR at the transcript level, and stabilized by OGT at the protein level. VPRBP knockdown in PCa cells led to a significant decrease in cell proliferation, p53 stabilization, nucleolar fragmentation and increased p53 recruitment to the chromatin. In human prostate tumor samples, VPRBP protein overexpression correlated with AR amplification, OGT overexpression, early biochemical relapse and poor clinical outcome. Analysis of TCGA datasets found a positive correlation of VPRBP with AR mRNA expression. Furthermore, AR activity gene signature analysis revealed a positive correlation of VPRBP with a subset of AR target genes implying that VPRBP has a preferential regulatory impact on part of the AR regulome. In conclusion, we have shown that VPRBP/DCAF1 promotes PCa cell proliferation by restraining p53 activation under the influence of the AR and OGT as well as uncovered a unique subset of AR activity gene signature that correlates with VPRBP expression with the potential for new avenues for patient stratification and treatment.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted July 04, 2021.
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VPRBP functions downstream of the androgen receptor and OGT to restrict p53 activation in prostate cancer
Ninu Poulose, Nicholas Forsythe, Adam Polonski, Gemma Gregg, Sarah Maguire, Marc Fuchs, Sarah Minner, Guido Sauter, Simon S. McDade, Ian G. Mills
bioRxiv 2021.02.28.433236; doi: https://doi.org/10.1101/2021.02.28.433236
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VPRBP functions downstream of the androgen receptor and OGT to restrict p53 activation in prostate cancer
Ninu Poulose, Nicholas Forsythe, Adam Polonski, Gemma Gregg, Sarah Maguire, Marc Fuchs, Sarah Minner, Guido Sauter, Simon S. McDade, Ian G. Mills
bioRxiv 2021.02.28.433236; doi: https://doi.org/10.1101/2021.02.28.433236

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