MTOR/MYCAxis regulates O-GlcNAc transferase expression and O-GlcN acylation in breast cancer

Valerie L. Sodi, Sakina Khaku, Raisa Krutilina, Luciana P. Schwab, David J. Vocadlo, Tiffany Seagroves, Mauricio J. Reginato

Research output: Contribution to journalArticle

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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-b-N-acetylglucosamine (OGlcNAc) 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.

Original languageEnglish (US)
Pages (from-to)923-933
Number of pages11
JournalMolecular Cancer Research
Volume13
Issue number5
DOIs
StatePublished - May 1 2015

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Acylation
Breast Neoplasms
Neoplasms
Glutamine
Phosphatidylinositol 3-Kinases
O-GlcNAc transferase
Hexosamines
Glucose
Proteins
Acetylglucosamine
Biosynthetic Pathways
Transgenic Mice
Carcinogenesis
Transcription Factors
Epithelial Cells
RNA

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Oncology
  • Cancer Research

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MTOR/MYCAxis regulates O-GlcNAc transferase expression and O-GlcN acylation in breast cancer. / Sodi, Valerie L.; Khaku, Sakina; Krutilina, Raisa; Schwab, Luciana P.; Vocadlo, David J.; Seagroves, Tiffany; Reginato, Mauricio J.

In: Molecular Cancer Research, Vol. 13, No. 5, 01.05.2015, p. 923-933.

Research output: Contribution to journalArticle

Sodi, Valerie L. ; Khaku, Sakina ; Krutilina, Raisa ; Schwab, Luciana P. ; Vocadlo, David J. ; Seagroves, Tiffany ; Reginato, Mauricio J. / MTOR/MYCAxis regulates O-GlcNAc transferase expression and O-GlcN acylation in breast cancer. In: Molecular Cancer Research. 2015 ; Vol. 13, No. 5. pp. 923-933.
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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-b-N-acetylglucosamine (OGlcNAc) 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.",
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AU - Schwab, Luciana P.

AU - Vocadlo, David J.

AU - Seagroves, Tiffany

AU - Reginato, Mauricio J.

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