title: mTOR/MYC Axis Regulates O-GlcNAc Transferase Expression and O-GlcNAcylation in Breast Cancer.
abstract: Cancers exhibit altered metabolism characterized by increased glucose and glutamine uptake. The hexosamine biosynthetic pathway (HBP) uses glucose and glutamine, and directly contributes to O-linked-β-N-acetylglucosamine (O-GlcNAc) modifications on intracellular proteins. Multiple tumor types contain elevated total O-GlcNAcylation, in part, by increasing O-GlcNAc transferase (OGT) levels, the enzyme that catalyzes this modification. Although cancer cells require OGT for oncogenesis, it is not clear how tumor cells regulate OGT expression and O-GlcNAcylation. Here, it is shown that the PI3K-mTOR-MYC signaling pathway is required for elevation of OGT and O-GlcNAcylation in breast cancer cells. Treatment with PI3K and mTOR inhibitors reduced OGT protein expression and decreased levels of overall O-GlcNAcylation. In addition, both AKT and mTOR activation is sufficient to elevate OGT/O-GlcNAcylation. Downstream of mTOR, the oncogenic transcription factor c-MYC is required and sufficient for increased OGT protein expression in an RNA-independent manner and c-MYC regulation of OGT mechanistically requires the expression of c-MYC transcriptional target HSP90A. Finally, mammary tumor epithelial cells derived from MMTV-c-myc transgenic mice contain elevated OGT and O-GlcNAcylation and OGT inhibition in this model induces apoptosis. Thus, OGT and O-GlcNAcylation levels are elevated via activation of an mTOR/MYC cascade.
  
  
  CONCLUSIONS
  Evidence indicates OGT as a therapeutic target in c-MYC-amplified cancers.
authors: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania.
authors: Valerie L
authors: VL
authors: Sodi
authors: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania.
authors: Sakina
authors: S
authors: Khaku
authors: Center for Adult Cancer Research and the Department of Pathology and Laboratory Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee.
authors: Raisa
authors: R
authors: Krutilina
authors: Center for Adult Cancer Research and the Department of Pathology and Laboratory Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee.
authors: Luciana P
authors: LP
authors: Schwab
authors: Department of Chemistry, Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
authors: David J
authors: DJ
authors: Vocadlo
authors: Center for Adult Cancer Research and the Department of Pathology and Laboratory Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee.
authors: Tiffany N
authors: TN
authors: Seagroves
authors: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania. mauricio.reginato@drexelmed.edu.
authors: Mauricio J
authors: MJ
authors: Reginato
mesh_terms: D000215:Acylation; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008822:Mice, Transgenic; D017351:N-Acetylglucosaminyltransferases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; C063057:UDP-N-acetylglucosamine-peptide beta-N-acetylglucosaminyltransferase; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
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