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UAP1 is overexpressed in prostate cancer and is protective against inhibitors of N-linked glycosylation

Oncogene volume 34, pages 3744–3750 (2015)Cite this article

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Abstract

Prostate cancer is the second most common cause of cancer-associated deaths in men, and signaling via a transcription factor called androgen receptor (AR) is an important driver of the disease. Consequently, AR target genes are prominent candidates to be specific for prostate cancer and also important for the survival of the cancer cells. Here we assess the levels of all hexosamine biosynthetic pathway (HBP) enzymes in 15 separate clinical gene expression data sets and identify the last enzyme in the pathway, UDP-N-acetylglucosamine pyrophosphorylase 1 (UAP1), to be highly overexpressed in prostate cancer. We analyzed 3261 prostate cancers on a tissue microarray and found that UAP1 staining correlates negatively with Gleason score (P=0.0039) and positively with high AR expression (P<0.0001). Cells with high UAP1 expression have 10-fold increased levels of the HBP end-product, UDP-N-acetylglucosamine (UDP-GlcNAc). UDP-GlcNAc is essential for N-linked glycosylation occurring in the endoplasmic reticulum (ER) and high UAP1 expression associates with resistance against inhibitors of N-linked glycosylation (tunicamycin and 2-deoxyglucose) but not with a general ER stress-inducing agent, the calcium ionophore A23187. Knockdown of UAP1 expression re-sensitized cells towards inhibitors of N-linked glycosylation, as measured by proliferation and activation of ER stress markers. Taken together, we have identified an enzyme, UAP1, which is highly overexpressed in prostate cancer and protects cancer cells from ER stress conferring a growth advantage.

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Acknowledgements

HMI is funded by an Early Stage Researcher fellowship as part of the EU FP7 Marie Curie Integrated Training Network, PRO-NEST (Prostate Research Organizations – Network Early Stage Training) Norwegian Cancer Society and Finnish Cultural Foundation. IGM is supported by funding from the Norwegian Research Council, Helse and the University of Oslo through the Centre for Molecular Medicine (Norway), which is a part of the Nordic EMBL (European Molecular Biology Laboratory) partnership. IGM is also supported by the Norwegian Cancer Society and by EU FP7 funding. IGM holds a visiting scientist position with Cancer Research UK through the Cambridge Research Institute and a Senior Visiting Research Fellowship with Cambridge University through the Department of Oncology. We thank Professor Olli Kallioniemi’s group (Institute for Molecular Medicine Finland, Helsinki, Finland) for technical support.

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Authors and Affiliations

  1. Prostate Cancer Research Group, Centre for Molecular Medicine (Norway), University of Oslo and Oslo University Hospitals, Oslo, Norway

    H M Itkonen, N Engedal, M Luhr, I J Guldvik & I G Mills

  2. The Biotechnology Center of Oslo, University of Oslo, Oslo, Norway

    E Babaie

  3. Institute for Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    S Minner, J Hohloch & M C Tsourlakis

  4. Department of Urology, Section for translational Prostate Cancer Research University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    T Schlomm

  5. Martini Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    T Schlomm

  6. Department of Cancer Prevention, Oslo University Hospitals, Oslo, Norway

    I G Mills

  7. Department of Urology, Oslo University Hospitals, Oslo, Norway

    I G Mills

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  1. H M Itkonen
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Itkonen, H., Engedal, N., Babaie, E. et al. UAP1 is overexpressed in prostate cancer and is protective against inhibitors of N-linked glycosylation. Oncogene 34, 3744–3750 (2015). https://doi.org/10.1038/onc.2014.307

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