UAP1 is overexpressed in prostate cancer and is protective against inhibitors of N-linked glycosylation
- 22 September 2014
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 34 (28), 3744-3750
- https://doi.org/10.1038/onc.2014.307
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.Keywords
This publication has 49 references indexed in Scilit:
- The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesisThe EMBO Journal, 2011
- Gene expression of O-GlcNAc cycling enzymes in human breast cancersClinical and Experimental Medicine, 2011
- O-GlcNAcylation is a novel regulator of lung and colon cancer malignancyBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2011
- Selective autophagy mediated by autophagic adapter proteinsAutophagy, 2011
- 2-Deoxy-d-glucose activates autophagy via endoplasmic reticulum stress rather than ATP depletionCancer Chemotherapy and Pharmacology, 2010
- O-linked β-N-acetylglucosamine (O-GlcNAc): Extensive crosstalk with phosphorylation to regulate signaling and transcription in response to nutrients and stressBiochimica et Biophysica Acta (BBA) - General Subjects, 2009
- Metabolomic profiles delineate potential role for sarcosine in prostate cancer progressionNature, 2009
- Under normoxia, 2-deoxy-d-glucose elicits cell death in select tumor types not by inhibition of glycolysis but by interfering with N-linked glycosylationMolecular Cancer Therapeutics, 2007
- Metabolic Syndrome in Men With Prostate Cancer Undergoing Long-Term Androgen-Deprivation TherapyJournal of Clinical Oncology, 2006
- Hexosamines Are Unlikely to Function as a Nutrient-Sensor in 3T3-L1 Adipocytes: A Comparison of UDP-Hexosamine Levels after Increased Glucose Flux and Glucosamine TreatmentEndocrine, 2004