Journal article
mTOR/MYC Axis Regulates O-GlcNAc Transferase Expression and O-GlcNAcylation in Breast Cancer
Molecular cancer research, v 13(5), pp 923-933
May 2015
PMID: 25636967
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
Evidence indicates OGT as a therapeutic target in c-MYC-amplified cancers.
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Details
- Title
- mTOR/MYC Axis Regulates O-GlcNAc Transferase Expression and O-GlcNAcylation in Breast Cancer
- Creators
- Valerie L Sodi - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PennsylvaniaSakina Khaku - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PennsylvaniaRaisa Krutilina - Center for Adult Cancer Research and the Department of Pathology and Laboratory Medicine, The University of Tennessee Health Science Center, Memphis, TennesseeLuciana P Schwab - Center for Adult Cancer Research and the Department of Pathology and Laboratory Medicine, The University of Tennessee Health Science Center, Memphis, TennesseeDavid J Vocadlo - Department of Chemistry, Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, CanadaTiffany N Seagroves - Center for Adult Cancer Research and the Department of Pathology and Laboratory Medicine, The University of Tennessee Health Science Center, Memphis, TennesseeMauricio J Reginato - Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania. mauricio.reginato@drexelmed.edu
- Publication Details
- Molecular cancer research, v 13(5), pp 923-933
- Publisher
- American Association for Cancer Research (AACR); United States
- Grant note
- R01 CA155413 / NCI NIH HHS R01 CA138488 / NCI NIH HHS R01CA138488 / NCI NIH HHS R01CA155413 / NCI NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000358057500012
- Scopus ID
- 2-s2.0-84942321625
- Other Identifier
- 991014878015104721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Cell Biology
- Oncology