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

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.

Fig. 1

High-fat diet reprograms prostate cancer metabolome and accelerates disease progression. a Mice fed a high-fat diet (HFD) develop diet-induced obesity at 12 weeks of age (n = biologically independent animals; two-way ANOVA, median, whiskers ± min/max; ****P < 0.0001). b–d HFD does not alter the penetrance of prostatic intraepithelial neoplasia (PIN) at 12 weeks of age (b, n = biologically independent lobes; unpaired t test, mean ± s.d.; CTD: control diet; AP: anterior prostate; DLP: dorsolateral prostate; VP: ventral prostate; ns: non significant), but does lead to a greater tumour burden (c, n = biologically independent lobes; Welch’s t test, mean ± s.d.; ****P < 0.0001) and to cell proliferation, as assessed by Ki-67 (d, n = biologically independent lobes; unpaired t test, median, whiskers ± min/max) in the VP, at 36 weeks of age. e Principal component analysis identifies a distinct metabolic profile in the VP that is triggered by HFD, in a MYC context (n = 6 biologically independent VP/condition, 414 metabolites detected). f, g Representation of all metabolites significantly altered by HFD in a WT (n = 12) or a MYC (n = 89) context, or by MYC overexpression irrespective of the diet (n = 214) (f, unsupervised hierarchical clustering, P < 0.05 and FDR < 0.15); the breakdown of metabolite classes is shown g. h Metabolite Set Enrichment Analysis (MSEA) revealed metabolic pathways significantly enriched by HFD in MYC-transformed VP (P < 0.05 and FDR < 0.15). i Metabolic rewiring triggered by MYC and by HFD in a MYC context suggests dampened histone methylation. Hcy: homocysteine (undetected); Met: methionine; TCA: tricarboxylic acid (citric acid cycle); Gln: glutamine; Glu: glutamate. Source data are provided as a Source Data file

Fig. 2

High-fat diet enhances MYC-driven transcriptional changes at H4K20me1 dynamic genes. a Global chromatin profiling identifies distinct chromatin-signature profiles in MYC-overexpressing DLP and VP lobes (histone marks levels relative to the DLP, VP and AP CTD_WT median values; MYC vs. WT comparisons, unpaired t test; *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001; Supplementary Data 6). b HFD enhances H4K20 hypomethylation triggered by MYC (MYC vs. WT and HFD_MYC vs. CTD_MYC comparisons, unpaired t test; *P < 0.05, **P < 0.01, ****P < 0.0001). c H4K20me0 levels relative to the CTD_WT condition (fold change; unpaired t test, mean ± SEM; **P < 0.01, ***P < 0.001, ****P < 0.0001). d H4K20me1 dynamic regions across all murine gene bodies relative to the CTD_WT condition. e HFD enhances the effect of MYC on gene expression at H4K20me1 dynamic regions that were lost (top, n = 2508 genes) or gained (bottom, n = 3208 genes; paired t test, median, whiskers ± min/max)

Fig. 3

High-fat diet enhances MYC transcriptional activity. a Gene Set Enrichment Analysis (GSEA, Hallmark, P < 0.05 and FDR < 0.1) revealed enhanced expression of MYC target genes triggered by HFD in the MYC context (right column-left side: HFD_MYC vs. CTD_MYC; right column-right side: HFD_WT vs. CTD_WT comparisons; left column: CTD_MYC vs. CTD_WT comparison). b HFD boosts the expression of the murine prostatic-derived MYC signature (n = 610 genes; fold-change relative to the CTD_WT condition, paired t test, median, whiskers ± min/max; ****P < 0.0001). c Increased PHF8 recruitment at the promoter (grey; −270 to −210 bp) of MYC signature genes, is triggered by MYC overexpression and boosted by HFD (fold-change relative to the CTD_WT condition, paired t test, mean ± SEM; ****P < 0.0001). d Depletion in H4K20me1 mark at the promoter of MYC signature genes (grey) requires increased PHF8 recruitment together with HFD (paired t test, mean ± SEM; ****P < 0.0001). e Representative PHF8 and H4K20me1 tracks at Rplp2 promoter (arrow), a MYC signature leading edge gene (RPM/bp: reads per million/base pair)

Fig. 4

A saturated fat-induced MYC signature is associated with lethal prostate cancer. a, b GSEA analysis (Hallmark) revealed that high animal fat and high saturated fat intake enriches for the MYC_targets_V1 gene set (a, P < 0.05 and FDR < 0.1), as represented by the enrichment plot (b) in the HSPH/PHS cohorts. c The lethality for every 0.1 unit increase of MYC score was significantly elevated among patients with high saturated fat intake compared with those with low saturated fat intake. d High expression of the saturated fat-induced MYC signature is significantly associated with reduced metastatic-free survival (T3) in four independent cohorts (TJU/JHMI-I/Mayo Clinic/Cedar-Sinai cohorts, n = 631). e Short-term dietary intervention (HFD switch to CTD) dampens the HFD-induced MYC transcriptional activity in MYC-driven murine prostate cancer. f Graphical summary