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. Den, Jonathan 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 () and Myles Brown ()
Additional contact information
David P. Labbé: Harvard Medical School
Giorgia Zadra: Dana-Farber Cancer Institute
Meng Yang: Harvard T.H. Chan School of Public Health
Jaime M. Reyes: Harvard Medical School
Charles Y. Lin: Baylor College of Medicine
Stefano Cacciatore: Cancer Genomics Group, International Centre for Genetic Engineering and Biotechnology
Ericka M. Ebot: Harvard T.H. Chan School of Public Health
Amanda L. Creech: The Broad Institute of MIT and Harvard University
Francesca Giunchi: Pathology Service, Addarii Institute of Oncology, S-Orsola-Malpighi Hospital
Michelangelo Fiorentino: Pathology Service, Addarii Institute of Oncology, S-Orsola-Malpighi Hospital
Habiba Elfandy: Dana-Farber Cancer Institute
Sudeepa Syamala: Dana-Farber Cancer Institute
Edward D. Karoly: Metabolon
Mohammed Alshalalfa: Decipher Biosciences
Nicholas Erho: Decipher Biosciences
Ashley Ross: Johns Hopkins Medical Institutions
Edward M. Schaeffer: Northwestern University Feinberg School of Medicine
Ewan A. Gibb: Decipher Biosciences
Mandeep Takhar: Decipher Biosciences
Robert B. Den: Sidney Kimmel Medical College at Thomas Jefferson University
Jonathan Lehrer: Decipher Biosciences
R. Jeffrey Karnes: Mayo Clinic Rochester
Stephen J. Freedland: Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center
Elai Davicioni: Decipher Biosciences
Daniel E. Spratt: University of Michigan
Leigh Ellis: Dana-Farber Cancer Institute
Jacob D. Jaffe: The Broad Institute of MIT and Harvard University
Anthony V. DʼAmico: Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School
Philip W. Kantoff: Harvard Medical School
James E. Bradner: Harvard Medical School
Lorelei A. Mucci: Harvard T.H. Chan School of Public Health
Jorge E. Chavarro: Harvard T.H. Chan School of Public Health
Massimo Loda: Dana-Farber Cancer Institute
Myles Brown: Harvard Medical School

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12298-z

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