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

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

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation / physiology
  • Female
  • Forkhead Box Protein M1 / genetics
  • Forkhead Box Protein M1 / metabolism*
  • Glycosylation
  • Heterografts
  • Humans
  • MCF-7 Cells
  • Mice
  • Mice, Inbred NOD
  • N-Acetylglucosaminyltransferases / metabolism*
  • Neoplasm Metastasis
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism*

Substances

  • FOXM1 protein, human
  • Forkhead Box Protein M1
  • N-Acetylglucosaminyltransferases
  • O-GlcNAc transferase
  • SIRT1 protein, human
  • Sirtuin 1