Great strides have been made in recent years in advancing our understanding of diet-gene interactions and their influence on cancer development. In the burgeoning field of epigenetics, an increased understanding of the mechanisms that regulate gene expression has produced a paradigm shift in how we consider cancer etiology and the relevant molecular biomarkers for cancer prevention. In contrast to genetic alterations, epigenetic marks are potentially reversible, making them promising targets for both cancer prevention and therapy. Researchers have identified new and novel epigenetic mechanisms for many candidate dietary chemoprevention agents. However, control of gene expression often requires the cooperation, interaction, and interplay among multiple epigenetic mechanisms. For example, the relationship between DNA methylation and chromatin remodeling suggests significant cross-talk among distinct epigenetic pathways that control gene silencing/unsilencing. Indeed, the combination of pharmacological DNMT inhibitors and HDAC inhibitors has been explored as a potential antitumor therapy (166
). However, both HDAC and DNMT inhibitor drugs have potential hazards and side effects, including cardiotoxicity in some clinical scenarios (168
). Interestingly, several miRNA are known to be regulated by DNA methylation status in cells. In a recent study, up to one-third of dysregulated miRNA loci showed consistent patterns of DNA methylation and H3K9 acetylation (170
), highlighting the complex interplay among multiple epigenetic regulators. Dovetailing this work with mechanistic studies of dietary epigenetic modulators deserves greater attention. In particular, understanding the relevant doses, timing, and possibly synergy and/or antagonism of various epigenetic marks to coordinate biological effects is of utmost importance.
To complicate matters, there is also significant interplay between genetic and epigenetic targets. For example, the traditional dogma for chemoprotection by SFN considered reactive thiol groups in Keap1 as key targets, promoting Nrf2 dissociation, nuclear trafficking, and activation of ARE-driven gene expression. Recent studies, however, have found that Nrf2 itself is under epigenetic regulation. Yu et al. (171
) demonstrated that Nrf2 expression was suppressed in prostate tumors derived from TRAMP mice. Moreover, silencing of Nrf2
was attributed to both promoter hypermethylation and histone modifications. Pharmacological DNMT inhibitors and/or HDAC inhibitors restored the expression and activity of Nrf2
). Thus, dietary agents such as SFN may coordinate Nrf2 activation at the epigenetic/chromatin level in addition to effects on Keap1. As we move forward, the lines between diet-genome and diet-epigenome interactions are becoming increasingly blurred. Individual susceptibility to disease and efficacy of specific nutrients and phytochemicals may be determined by a combination of both genetic and epigenetic control mechanisms. No doubt, these will be important issues in the future development of better optimized dietary chemoprevention strategies.
Understanding the precise actions of dietary bioactive nutrients in cancer prevention is a complicated and difficult task. Many such compounds exhibit pleiotropic effects, which can be viewed as either beneficial or deleterious. Advocates consider the benefit of targeting multiple players along the pathway to malignancy, whereas skeptics typically cite potential “off-target” concerns. For many nutrients, the relative priority of genetic compared to epigenetic mechanisms remains poorly defined. Importantly, additional research on dose, metabolism, timing, and tissue specificity is sorely needed. It is possible that doses that optimally target epigenetics may not target other known genetic targets and vice versa. Establishing dose responses, including possible toxicities, will be extremely important prior to making recommendations. Nonetheless, targeting the epigenome with modifiers of miRNA, DNA methylation, and histone marks provides an attractive avenue for future research, with considerable promise for cancer clinical trials. Identification of dietary epigenetic modulators and their clinical application, either alone or in combination, may enhance the efficacy of ongoing anticancer therapies/prevention strategies while reducing the unwanted side effects.