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.
Highlights
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
Increased tumour weight (Fig. 1c) and cell proliferation (Ki-67; Fig. 1d) were evident by 36 weeks of age in the high-fat diet (HFD)-fed mice compared to the control diet (CTD) group, confirming previous reports that HFD significantly enhances the progression of MYC-driven prostate cancer[10,11]
HFD impacts metabolites that are primarily restricted to membrane lipid remodelling, has little influence on histone modifications, and results in a distinct transcriptional program compared to that induced by HFD in the transformed prostate
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. 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 associated with an enhanced MYC transcriptional signature in prostate cancer patients. Epidemiological studies have reported that saturated fat intake and obesity are associated with increased prostate cancer progression and mortality[2,3,4,5]. The influence of metabolic alterations triggered by increased fat intake and/or obesity on prostate cancer epigenome rewiring and disease progression is still unexplored. MYC over expression faithfully recapitulates the primary human disease[21]
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