Role of diet in prostate cancer: the epigenetic link

Abstract

Diet is hypothesized to be a critical environmentally related risk factor for prostate cancer (PCa) development, and specific diets and dietary components can also affect PCa progression; however, the mechanisms underlying these associations remain elusive. As for a maturing organism, PCa's epigenome is plastic and evolves from the pre-neoplastic to the metastatic stage. In particular, epigenetic remodeling relies on substrates or cofactors obtained from the diet. Here we review the evidence that bridges dietary modulation to alterations in the prostate epigenome. We propose that such diet-related effects offer a mechanistic link between the impact of different diets and the course of PCa development and progression.

Figure 1

From metabolism to epigenetic remodeling. (a) SIRT1 activity depends on the NAD⁺/NADH ratio modulated by glycolysis, while O-linked N-acetylglucosamine transferase uses GlcNAc produced by the hexosamine pathway. Pyruvate entering the tricarboxylic acid (TCA) cycle produces alpha-ketoglutarate, a critical cofactor for Jumonji domain-containing histone demethylase and TET. Acetyl-CoA is converted from the citrate generated by the TCA cycle and used as a donor by histone acetyltransferases. Finally, the increase in ATP/ADP ratio from the TCA cycle also inactivates AMPK. (b) SAM acts as a methyl donor for histone methyltransferases and TET and is obtained through the coordinate action of the folate and methionine cycles, termed one-carbon metabolism. αKG: Alpha-ketoglutarate; AMPK: 5′ AMP–activated protein kinase; ADP: adenosine diphosphate; ATP: adenosine triphosphate; B₂: vitamin B₂; B₆: vitamin B₆; B₁₂: vitamin B₁₂; DHF: dihydrofolate; DMG: dimethylglycine; DNMT: DNA methyltransferases; GlcNAc: N-acetylglucosamine; HAT: histone acetyltransferases; Hcy: homocystein; HMT: histone methyltransferases; JHDM: Jumonji domain-containing histone demethylase; OGT: O-linked N-acetylglucosamine transferase; me-THF: 5,10-methylenetetrahydrofolate; Met: methionine; mTHF: 5-methyltetrahydrofolate; NAD+: nicotinamide adenine dinucleotide (oxidized); NADH: nicotinamide adenine dinucleotide (reduced); SAH: S-adenosylhomocysteine; SAM: S-adenosylmethionine; SIRT1: sirtuin histone deacetylase 1; TCA: tricarboxylic acid; TET: ten eleven translocation; THF: tetrahydrofolate.