title: UAP1 is overexpressed in prostate cancer and is protective against inhibitors of N-linked glycosylation.
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.
authors.affiliation: Prostate Cancer Research Group, Centre for Molecular Medicine (Norway), University of Oslo and Oslo University Hospitals, Oslo, Norway.
authors.forename: H M
authors.initials: HM
authors.lastname: Itkonen
authors.affiliation: Prostate Cancer Research Group, Centre for Molecular Medicine (Norway), University of Oslo and Oslo University Hospitals, Oslo, Norway.
authors.forename: N
authors.initials: N
authors.lastname: Engedal
authors.affiliation: The Biotechnology Center of Oslo, University of Oslo, Oslo, Norway.
authors.forename: E
authors.initials: E
authors.lastname: Babaie
authors.affiliation: Prostate Cancer Research Group, Centre for Molecular Medicine (Norway), University of Oslo and Oslo University Hospitals, Oslo, Norway.
authors.forename: M
authors.initials: M
authors.lastname: Luhr
authors.affiliation: Prostate Cancer Research Group, Centre for Molecular Medicine (Norway), University of Oslo and Oslo University Hospitals, Oslo, Norway.
authors.forename: I J
authors.initials: IJ
authors.lastname: Guldvik
authors.affiliation: Institute for Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Minner
authors.affiliation: Institute for Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Hohloch
authors.affiliation: Institute for Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: M C
authors.initials: MC
authors.lastname: Tsourlakis
authors.affiliation: 1] Department of Urology, Section for translational Prostate Cancer Research University Medical Center Hamburg-Eppendorf, Hamburg, Germany [2] Martini Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Schlomm
authors.affiliation: 1] Prostate Cancer Research Group, Centre for Molecular Medicine (Norway), University of Oslo and Oslo University Hospitals, Oslo, Norway [2] Department of Cancer Prevention, Oslo University Hospitals, Oslo, Norway [3] Department of Urology, Oslo University Hospitals, Oslo, Norway.
authors.forename: I G
authors.initials: IG
authors.lastname: Mills
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003847:Deoxyglucose / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005700:Galactosyltransferases / Q000378:metabolism*; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011944:Receptors, Androgen / Q000378:metabolism; D046888:Tissue Array Analysis / Q000379:methods; D014415:Tunicamycin / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: C410798:AR protein, human; D011944:Receptors, Androgen; D014415:Tunicamycin; D003847:Deoxyglucose; D005700:Galactosyltransferases; C511281:UDP-GalNAc pyrophosphorylase AGX1, human