title: O-GlcNAc transferase integrates metabolic pathways to regulate the stability of c-MYC in human prostate cancer cells.
abstract: Metabolic disruptions that occur widely in cancers offer an attractive focus for generalized treatment strategies. The hexosamine biosynthetic pathway (HBP) senses metabolic status and produces an essential substrate for O-linked β-N-acetylglucosamine transferase (OGT), which glycosylates and thereby modulates the function of its target proteins. Here, we report that the HBP is activated in prostate cancer cells and that OGT is a central regulator of c-Myc stability in this setting. HBP genes were overexpressed in human prostate cancers and androgen regulated in cultured human cancer cell lines. Immunohistochemical analysis of human specimens (n = 1987) established that OGT is upregulated at the protein level and that its expression correlates with high Gleason score, pT and pN stages, and biochemical recurrence. RNA interference-mediated siliencing or pharmacologic inhibition of OGT was sufficient to decrease prostate cancer cell growth. Microarray profiling showed that the principal effects of OGT inhibition in prostate cancer cells were related to cell-cycle progression and DNA replication. In particular, c-MYC was identified as a candidate upstream regulator of OGT target genes and OGT inhibition elicited a dose-dependent decrease in the levels of c-MYC protein but not c-MYC mRNA in cell lines. Supporting this relationship, expression of c-MYC and OGT was tightly correlated in human prostate cancer samples (n = 1306). Our findings identify HBP as a modulator of prostate cancer growth and c-MYC as a key target of OGT function in prostate cancer cells.
authors.affiliation: Prostate Research Group, Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway.
authors.forename: Harri M
authors.initials: HM
authors.lastname: Itkonen
authors.forename: Sarah
authors.initials: S
authors.lastname: Minner
authors.forename: Ingrid J
authors.initials: IJ
authors.lastname: Guldvik
authors.forename: Mareike Julia
authors.initials: MJ
authors.lastname: Sandmann
authors.forename: Maria Christina
authors.initials: MC
authors.lastname: Tsourlakis
authors.forename: Viktor
authors.initials: V
authors.lastname: Berge
authors.forename: Aud
authors.initials: A
authors.lastname: Svindland
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schlomm
authors.forename: Ian G
authors.initials: IG
authors.lastname: Mills
mesh_terms: D000728:Androgens / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004261:DNA Replication / Q000187:drug effects; D006595:Hexosamines / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways; D017351:N-Acetylglucosaminyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: C410798:AR protein, human; D000728:Androgens; D014408:Biomarkers, Tumor; D006595:Hexosamines; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D011944:Receptors, Androgen; D054852:Small Molecule Libraries; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; C063057:UDP-N-acetylglucosamine-peptide beta-N-acetylglucosaminyltransferase