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

Autor: Ferrer CM; Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA., Lu TY; Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA., Bacigalupa ZA; Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA., Katsetos CD; 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., Sinclair DA; Paul F. Glenn Labs for the Biological Mechanisms of Aging, Department of Genetics, Harvard Medical School, Boston, MA, USA., Reginato MJ; Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2017 Jan 26; Vol. 36 (4), pp. 559-569. Date of Electronic Publication: 2016 Jun 27.
DOI: 10.1038/onc.2016.228
Abstrakt: 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.
Competing Interests: D.A.S. is a consultant to GlaxoSmithKline, Segterra, Ovascience, and MetroBiotech. The authors declare no conflict of interest.
Databáze: MEDLINE
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