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

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 m...

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Published in:Nature communications Vol. 10; no. 1; pp. 4358 - 14
Main Authors: Labbé, David P., Zadra, Giorgia, Yang, Meng, Reyes, Jaime M., Lin, Charles Y., Cacciatore, Stefano, Ebot, Ericka M., Creech, Amanda L., Giunchi, Francesca, Fiorentino, Michelangelo, Elfandy, Habiba, Syamala, Sudeepa, Karoly, Edward D., Alshalalfa, Mohammed, Erho, Nicholas, Ross, Ashley, Schaeffer, Edward M., Gibb, Ewan A., Takhar, Mandeep, Den, Robert B., Lehrer, Jonathan, Karnes, R. Jeffrey, Freedland, Stephen J., Davicioni, Elai, Spratt, Daniel E., Ellis, Leigh, Jaffe, Jacob D., DʼAmico, Anthony V., Kantoff, Philip W., Bradner, James E., Mucci, Lorelei A., Chavarro, Jorge E., Loda, Massimo, Brown, Myles
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 25.09.2019
Nature Publishing Group
Nature Portfolio
Subjects:
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631/67/2324
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64/60
692/4028/67/589/466
692/499
692/53/2422
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Aged
Animals
Cell Line, Tumor
Cell Proliferation - drug effects
Cell Proliferation - genetics
Diet
Diet, High-Fat - adverse effects
Disease Progression
Gene Expression Regulation, Neoplastic - drug effects
High fat diet
Humanities and Social Sciences
Humans
Low fat diet
Male
Metabolism
Metabolome - drug effects
Mice, Transgenic
Middle Aged
Mimicry
multidisciplinary
Myc protein
Nutrient deficiency
Prostate cancer
Prostatic Neoplasms - etiology
Prostatic Neoplasms - genetics
Prostatic Neoplasms - metabolism
Proto-Oncogene Proteins c-myc - genetics
Proto-Oncogene Proteins c-myc - metabolism
Rewiring
Science
Science (multidisciplinary)
Transcription
Tumor Burden - drug effects
Tumor Burden - genetics
Tumors
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary: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. Prostate cancer progression may be enhanced by a high-fat diet. Here the authors show that a diet high in saturated fats enhance the MYC-driven transcriptional program, a feature that independently predicts prostate cancer progression and death.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-019-12298-z