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

View ORCID ProfileNinu Poulose, Adam Polonski, Nicholas Forsythe, Gemma Gregg, View ORCID ProfileSarah Maguire, Marc Fuchs, View ORCID ProfileSarah Minner, 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: ninu.poulose@nds.ox.ac.uk
Adam Polonski
3University Medical Center Hamburg-Eppendorf Department of Pathology, Hamburg, Germany, 20246
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Nicholas Forsythe
1Patrick G Johnston Centre for Cancer Research, Queen’s University, Belfast, UK, BT9 7AE
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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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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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Abstract

Androgen receptor (AR) is a major driver of prostate cancer (PCa) initiation and progression. 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 PCa with its expression correlated with high Gleason score. In this study we have identified an AR and OGT co-regulated factor, VPRBP/DCAF1. We show that VPRBP is regulated by the AR at the transcript level, and by OGT at the protein level. In human tissue samples, VPRBP protein expression correlated with AR amplification, OGT overexpression and poor prognosis. VPRBP knockdown in prostate cancer cells led to a significant decrease in cell proliferation, p53 stabilization, nucleolar fragmentation and increased p53 recruitment to the chromatin. In conclusion, we have shown that VPRBP/DCAF1 promotes prostate cancer cell proliferation by restraining p53 activation under the influence of the AR and OGT.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
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 February 28, 2021.
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VPRBP functions downstream of the androgen receptor and OGT to restrict p53 activation in prostate cancer
Ninu Poulose, Adam Polonski, Nicholas Forsythe, Gemma Gregg, Sarah Maguire, Marc Fuchs, Sarah Minner, 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, Adam Polonski, Nicholas Forsythe, Gemma Gregg, Sarah Maguire, Marc Fuchs, Sarah Minner, 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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