Nutrient sensor O-GlcNAc transferase controls cancer lipid metabolism via SREBP-1 regulation

V. L. Sodi, Z. A. Bacigalupa, C. M. Ferrer, J. V. Lee, W. A. Gocal, D. Mukhopadhyay, K. E. Wellen, M. Ivan, M. J. Reginato

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10 Scopus citations

Abstract

Elevated O-GlcNAcylation is associated with disease states such as diabetes and cancer. O-GlcNAc transferase (OGT) is elevated in multiple cancers and inhibition of this enzyme genetically or pharmacologically inhibits oncogenesis. Here we show that O-GlcNAcylation modulates lipid metabolism in cancer cells. OGT regulates expression of the master lipid regulator the transcription factor sterol regulatory element binding protein 1 (SREBP-1) and its transcriptional targets both in cancer and lipogenic tissue. OGT regulates SREBP-1 protein expression via AMP-activated protein kinase (AMPK). SREBP-1 is critical for OGT-mediated regulation of cell survival and of lipid synthesis, as overexpression of SREBP-1 rescues lipogenic defects associated with OGT suppression, and tumor growth in vitro and in vivo. These results unravel a previously unidentified link between O-GlcNAcylation, lipid metabolism and the regulation of SREBP-1 in cancer and suggests a crucial role for O-GlcNAc signaling in transducing nutritional state to regulate lipid metabolism.

Original languageEnglish (US)
Pages (from-to)924-934
Number of pages11
JournalOncogene
Volume37
Issue number7
DOIs
StatePublished - Feb 15 2018

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ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Sodi, V. L., Bacigalupa, Z. A., Ferrer, C. M., Lee, J. V., Gocal, W. A., Mukhopadhyay, D., Wellen, K. E., Ivan, M., & Reginato, M. J. (2018). Nutrient sensor O-GlcNAc transferase controls cancer lipid metabolism via SREBP-1 regulation. Oncogene, 37(7), 924-934. https://doi.org/10.1038/onc.2017.395