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.