Ferrer, Christina M.Lu, Tong Y.Bacigalupa, Zachary A.Katsetos, Christos D.Sinclair, DavidReginato, Mauricio J.2017-01-032016Ferrer, Christina M., Tong Y. Lu, Zachary A. Bacigalupa, Christos D. Katsetos, David A. Sinclair, and Mauricio J. Reginato. 2016. “O-GlcNAcylation regulates breast cancer metastasis via SIRT1 modulation of FOXM1 pathway.” Oncogene :10.1038/onc.2016.228. doi:10.1038/onc.2016.228. http://dx.doi.org/10.1038/onc.2016.228.0950-9232http://nrs.harvard.edu/urn-3:HUL.InstRepos:29739011Tumors 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-dependent manner. Reduced O-GlcNAcylation in cancer cells leads to SIRT1-mediated proteasomal degradation of oncogenic transcription factor FOXM1 in a 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 a SIRT1/ /FOXM1 axis.en-USO-GlcNAcOGTsirtuinSIRT1FOXM1cancermetabolisminvasionmetastasisdeacetylationMEKERKAMPKJournal Article2017-01-0310.1038/onc.2016.228