title: O-GlcNAcylation regulates breast cancer metastasis via SIRT1 modulation of FOXM1 pathway.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Ferrer
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA.
authors.forename: T Y
authors.initials: TY
authors.lastname: Lu
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA.
authors.forename: Z A
authors.initials: ZA
authors.lastname: Bacigalupa
authors.affiliation: 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.
authors.forename: C D
authors.initials: CD
authors.lastname: Katsetos
authors.affiliation: Paul F. Glenn Labs for the Biological Mechanisms of Aging, Department of Genetics, Harvard Medical School, Boston, MA, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Sinclair
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Reginato
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D005260:Female; D000072278:Forkhead Box Protein M1 / Q000235:genetics / Q000378:metabolism*; D006031:Glycosylation; D064593:Heterografts; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D016688:Mice, Inbred NOD; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D009362:Neoplasm Metastasis; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; C447939:SIRT1 protein, human; D056564:Sirtuin 1