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Oncogene. 2017 Jan 26;36(4):559-569. doi: 10.1038/onc.2016.228. Epub 2016 Jun 27.

O-GlcNAcylation regulates breast cancer metastasis via SIRT1 modulation of FOXM1 pathway.

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Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA.
Department of Pathology and Laboratory Medicine, Drexel University College of Medicine, Philadelphia, PA, USA.
Department of Pediatrics, Drexel University College of Medicine, St. Christopher's Hospital for Children, Philadelphia, PA, USA.
Paul F. Glenn Labs for the Biological Mechanisms of Aging, Department of Genetics, Harvard Medical School, Boston, MA, USA.


Tumors utilize aerobic glycolysis to support growth and invasion. However, the molecular mechanisms that link metabolism with invasion are not well understood. The nutrient sensor O-linked-β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) modifies intracellular proteins with N-acetylglucosamine. Cancers display elevated O-GlcNAcylation and suppression of O-GlcNAcylation inhibits cancer invasion and metastasis. Here, we show that the regulation of cancer invasion by OGT is dependent on the NAD+-dependent deacetylase SIRT1. Reducing O-GlcNAcylation elevates SIRT1 levels and activity in an AMPK (AMP-activated protein kinase α)-dependent manner. Reduced O-GlcNAcylation in cancer cells leads to SIRT1-mediated proteasomal degradation of oncogenic transcription factor FOXM1 in an MEK/ERK-dependent manner. SIRT1 is critical for OGT-mediated regulation of FOXM1 ubiquitination and reducing SIRT1 activity reverses OGT-mediated regulation of FOXM1. Moreover, we show that SIRT1 levels are required for OGT-mediated regulation of invasion and metastasis in breast cancer cells. Thus, O-GlcNAcylation is a central component linking metabolism to invasion and metastasis via an SIRT1/ERK/FOXM1 axis.

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