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.

Lipid degradation promotes prostate cancer cell survival

“…AR-driven complex transcriptional programs have previously been used as a starting point to identify prostate cancer-specific metabolic vulnerabilities [28, 29]. In this study, we showed that ECI2, an enzyme involved in degradation of unsaturated lipids, is a direct AR-target and over-expressed in clinical prostate cancer (Figures 1 and 2).…”

Hallmarks of glycosylation in cancer

“…The c-MYC protein is known to be glycosylated [80], and has been shown to be stabilised by modification with O-GlcNAc [28]. Levels of O-GlcNAcylation are up-regulated in various types of cancer [45, 51], as are some of the enzymes involved in the hexosamine biosynthesis pathway [81]. Future studies will help determine whether O-GlcNAc mediated stabilisation of c-MYC can indirectly influence telomerase activation and contribute to replicative immortality.…”

GFAT1/HBP/O-GlcNAcylation Axis Regulatesβ-Catenin Activity to Promote Pancreatic Cancer Aggressiveness

“…By correlation analysis, we found that the HBP gene signature was closely associated with the tumor cell proliferation (Figure 2(a)) and metastasis (Figure 2(b)). GFAT1 is the first and rate-limiting enzyme of HBP; glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1) catalyzes the acetylation step of HBP [7]; UDP-N acetylglu-cosamine pyrophosphorylase 1 (UAP1) catalyzes the final enzymatic reaction of HBP [18], contributing to UDP-GlcNAc synthesis (Figure 2(c)). In PDAC, we revealed a slight increase of GNPNAT1 and UAP1 expression and a BioMed Research International significant overexpression of GFAT1 in tumor tissues compared with normal counterparts (Figure 2(d)).…”