UAP1 is overexpressed in prostate cancer and is protective against inhibitors of N-linked glycosylation
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UAP1 is overexpressed in prostate cancer and is protective against inhibitors of N-linked glycosylation. / Itkonen, H M; Engedal, N; Babaie, E; Luhr, M; Guldvik, I J; Minner, S; Hohloch, J; Tsourlakis, M C; Schlomm, T; Mills, I G.
in: ONCOGENE, Jahrgang 34, Nr. 28, 01.07.2015, S. 3744-50.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - UAP1 is overexpressed in prostate cancer and is protective against inhibitors of N-linked glycosylation
AU - Itkonen, H M
AU - Engedal, N
AU - Babaie, E
AU - Luhr, M
AU - Guldvik, I J
AU - Minner, S
AU - Hohloch, J
AU - Tsourlakis, M C
AU - Schlomm, T
AU - Mills, I G
PY - 2015/7/1
Y1 - 2015/7/1
N2 - 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.Oncogene advance online publication, 22 September 2014; doi:10.1038/onc.2014.307.
AB - 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.Oncogene advance online publication, 22 September 2014; doi:10.1038/onc.2014.307.
U2 - 10.1038/onc.2014.307
DO - 10.1038/onc.2014.307
M3 - SCORING: Journal article
C2 - 25241896
VL - 34
SP - 3744
EP - 3750
JO - ONCOGENE
JF - ONCOGENE
SN - 0950-9232
IS - 28
ER -