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

Oncogene volume 37, pages 924–934 (2018)Cite this article

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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.

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Acknowledgements

We thank Nicholas Xerri for technical support and Mignon Keaton for help in analyzing LC–MS metabolite data. This work was supported by NCI grants CA192868 (to VLS), CA183574 (to CMF) and CA155413 (to MJR).

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Authors and Affiliations

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

    V L Sodi, Z A Bacigalupa, C M Ferrer, W A Gocal, D Mukhopadhyay & M J Reginato

  2. Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    J V Lee & K E Wellen

  3. Department Medicine, Indiana University, Indianapolis, IN, USA

    M Ivan

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  1. V L Sodi
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  2. Z A Bacigalupa
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Correspondence to M J Reginato.

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Sodi, V., Bacigalupa, Z., Ferrer, C. et al. Nutrient sensor O-GlcNAc transferase controls cancer lipid metabolism via SREBP-1 regulation. Oncogene 37, 924–934 (2018). https://doi.org/10.1038/onc.2017.395

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