Abstract A10: High-fat diet enhances MYC-driven prostate cancer through epigenomic and metabolomic rewiring (2016)

Abstract Diet is hypothesized to be a critical environmental risk factor for prostate cancer (PCa) development, and progression; however, the mechanisms underlying these associations remain elusive. In a MYC-driven PCa mouse model we find that a high fat diet significantly alters the transcription of genes implicated in chromatin function and remodeling in prostatic tumor tissues but not in the normal prostate. Importantly, this chromatin associated gene expression signature was observed well before the appearance of a high fat diet-driven phenotype that was characterized by greater cell proliferation and increased tumor burden. Consistent with this finding, high-throughput targeted quantitative histone mass spectrometry revealed a robust MYC-driven signature affecting more than half of the 68 histone marks profiled. Surprisingly, high fat diet further enhanced the MYC-induced epigenetic signature while it was unable to affect the normal murine prostate. Epigenetic remodeling relies on substrates and cofactors that are obtained from the diet. Untargeted metabolomic analyses revealed that MYC overexpression, as expected, impacted glutamine uptake. In addition, high fat diet leads to additional carbohydrates, amino acids, lipids and nucleotides necessary to sustain an increased cellular proliferation in MYC-driven cancers while it had little influence on the normal prostate. Moreover, the pool of metabolites altered by high fat diet in the context of MYC overexpression is highly suggestive of a global methylation defect. Finally, using the genome-wide mRNA profiles of tumor (N=402) and adjacent normal (N=200) prostate tissues from the Health Professionals Follow-up Study and the Physicians' Health Study cohorts, we have discovered an enrichment in genes implicated in chromatin function and remodeling in tumor tissues from overweight/obese men, but not in normal adjacent tissues, consistent with the high fat diet signature observed in mice. Strikingly, men whose tumors had high expression of this chromatin signature had worse clinical characteristics and were more likely to die from prostate cancer (OR = 5.01; 95% CI = 2.31, 11.38 comparing extreme score quartiles). Taken together, these results demonstrate that a high fat diet does not drive significant epigenomic and metabolomic alterations in the normal prostate while it leads to important alterations in MYC-driven PCa that results in increased aggressiveness. Our results suggest that the impact of diet on PCa risk may be to augment the growth of already established subclinical disease. In addition, as MYC is one of the most commonly amplified genes in PCa, the ability of a high fat diet to augment MYC-driven cancers in this pre-clinical model suggest that a healthy diet may slow the progression of the disease. Citation Format: David P. Labbé, Giorgia Zadra, Ericka M. Ebot, Charles Y. Lin, Jaime M. Reyes, Stefano Cacciatore, Maura Cotter, Amanda L. Creech, Jacob D. Jaffe, Philip W. Kantoff, James E. Bradner, Lorelei A. Mucci, Massimo Loda, Myles Brown. High-fat diet enhances MYC-driven prostate cancer through epigenomic and metabolomic rewiring. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr A10.