mTOR/MYC Axis Regulates O-GlcNAc Transferase Expression and O-GlcNAcylation in Breast Cancer.

Abstract

UNLABELLED:

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.

IMPLICATIONS:

Evidence indicates OGT as a therapeutic target in c-MYC-amplified cancers.

• Authors: Valerie L Sodi, Sakina Khaku, Raisa Krutilina, Luciana P Schwab, David J Vocadlo, Tiffany N Seagroves, Mauricio J Reginato
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 13 Issue 5 Pg. 923-33 (May 2015) ISSN: 1557-3125 [Electronic] United States
• PMID: 25636967 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• MYC protein, human
• Proto-Oncogene Proteins c-myc
• N-Acetylglucosaminyltransferases
• O-GlcNAc transferase
• UDP-N-acetylglucosamine-peptide beta-N-acetylglucosaminyltransferase
• MTOR protein, human
• TOR Serine-Threonine Kinases

Topics

• Acylation
• Animals
• Apoptosis (physiology)
• Breast Neoplasms (enzymology, genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (physiology)
• Female
• Humans
• MCF-7 Cells
• Mice
• Mice, Transgenic
• N-Acetylglucosaminyltransferases (biosynthesis, genetics, metabolism)
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• TOR Serine-Threonine Kinases (genetics, metabolism)
• Transfection