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Nat Commun. 2019 Sep 25;10(1):4358. doi: 10.1038/s41467-019-12298-z.

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

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
2
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
3
Division of Urology, Department of Surgery, McGill University and Research Institute of the McGill University Health Centre, Montréal, QC, Canada.
4
Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
5
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
6
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
7
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
8
Cancer Genomics Group, International Centre for Genetic Engineering and Biotechnology, Cape Town, South Africa.
9
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
10
The Broad Institute of MIT and Harvard University, Cambridge, MA, USA.
11
Pathology Service, Addarii Institute of Oncology, S-Orsola-Malpighi Hospital, Bologna, IT, Italy.
12
Metabolon, Morrisville, NC, USA.
13
Decipher Biosciences, Vancouver, BC, Canada.
14
James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
15
Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
16
Department of Radiation Oncology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, USA.
17
Department of Urology, Mayo Clinic Rochester, Rochester, MN, USA.
18
Department of Surgery, Division of Urology, Center for Integrated Research on Cancer and Lifestyle, Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
19
Surgery Section, Durham Veteran Affairs Medical Center, Durham, NC, USA.
20
Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
21
Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
22
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
23
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
24
Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA. mloda@med.cornell.edu.
25
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. mloda@med.cornell.edu.
26
The Broad Institute of MIT and Harvard University, Cambridge, MA, USA. mloda@med.cornell.edu.
27
Department of Pathology and Laboratory Medicine, Weil Cornell Medicine, New York Presbyterian-Weill Cornell Campus, New York, NY, USA. mloda@med.cornell.edu.
28
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. myles_brown@dfci.harvard.edu.
29
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA. myles_brown@dfci.harvard.edu.

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.

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