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

Oncogene volume 36, pages 559–569 (2017)Cite this article

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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.

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Acknowledgements

We thank Valerie Sodi for critical reading of this manuscript. This work is supported by NCI grants CA183574 (to CMF), CA155413 (to MJR) and NIH/NIA grant AG028730 (to DAS).

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA

    C M Ferrer, T Y Lu, Z A Bacigalupa & M J Reginato

  2. Department of Pathology and Laboratory Medicine, Drexel University College of Medicine, Philadelphia, PA, USA

    C D Katsetos

  3. Department of Pediatrics, Drexel University College of Medicine, St. Christopher’s Hospital for Children, Philadelphia, PA, USA

    C D Katsetos

  4. Department of Genetics, Paul F. Glenn Labs for the Biological Mechanisms of Aging, Harvard Medical School, Boston, MA, USA

    D A Sinclair

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  1. C M Ferrer
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Correspondence to M J Reginato.

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Ferrer, C., Lu, T., Bacigalupa, Z. et al. O-GlcNAcylation regulates breast cancer metastasis via SIRT1 modulation of FOXM1 pathway. Oncogene 36, 559–569 (2017). https://doi.org/10.1038/onc.2016.228

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