High-fat diet fuels prostate cancer progression by rewiring the metabolome and amplifying the MYC program

David P. Labbé, Giorgia Zadra, Meng Yang, Jaime M. Reyes, Charles Y. Lin, Stefano Cacciatore, Ericka M. Ebot, Amanda L. Creech, Francesca Giunchi, Michelangelo Fiorentino, Habiba Elfandy, Sudeepa Syamala, Edward D. Karoly, Mohammed Alshalalfa, Nicholas Erho, Ashley Ross, Edward M. Schaeffer, Ewan A. Gibb, Mandeep Takhar, Robert B. DenJonathan Lehrer, R. Jeffrey Karnes, Stephen J. Freedland, Elai Davicioni, Daniel E. Spratt, Leigh Ellis, Jacob D. Jaffe, Anthony V. DʼAmico, Philip W. Kantoff, James E. Bradner, Lorelei A. Mucci, Jorge E. Chavarro, Massimo Loda, Myles Brown

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Systemic metabolic alterations associated with increased consumption of saturated fat and obesity are linked with increased risk of prostate cancer progression and mortality, but the molecular underpinnings of this association are poorly understood. Here, we demonstrate in a murine prostate cancer model, that high-fat diet (HFD) enhances the MYC transcriptional program through metabolic alterations that favour histone H4K20 hypomethylation at the promoter regions of MYC regulated genes, leading to increased cellular proliferation and tumour burden. Saturated fat intake (SFI) is also associated with an enhanced MYC transcriptional signature in prostate cancer patients. The SFI-induced MYC signature independently predicts prostate cancer progression and death. Finally, switching from a high-fat to a low-fat diet, attenuates the MYC transcriptional program in mice. Our findings suggest that in primary prostate cancer, dietary SFI contributes to tumour progression by mimicking MYC over expression, setting the stage for therapeutic approaches involving changes to the diet.

Original languageEnglish (US)
Article number4358
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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