Epigenetics Offer New Horizons for Colorectal Cancer Prevention

Abstract

In recent years, colorectal cancer (CRC) incidence has been increasing to become a major cause of morbidity and mortality worldwide from cancers, with high rates in westernized societies and increasing rates in developing countries. Epigenetic modifications including changes in DNA methylation, histone modifications, and non-coding RNAs play a critical role in carcinogenesis. Epidemiological data suggest that, in comparison to other cancers, these alterations are particularly common within the gastrointestinal tract. To explain these observations, environmental factors and especially diet were suggested to both prevent and induce CRC. Epigenetic alterations are, in contrast to genetic modifications, potentially reversible, making the use of dietary agents a promising approach in CRC for the development of chemopreventive strategies targeting epigenetic mechanisms. This review focuses on CRC-related epigenetic alterations as a rationale for various levels of prevention strategies and their potential modulation by natural dietary compounds.

Fig. 1

Colorectal cancer (CRC) progression as a model for epigenetic alteration cascade and prevention strategies. CRC development is initially starting by a premalignant lesion, called aberrant crypt foci (ACF), rising from normal colonic mucosa, progressing to a premalignant lesion (adenoma) and then to invasive adenocarcinoma, and finally evolving to metastatic adenocarcinoma. Epigenetic alterations are largely contributing to CRC initiation and adenoma-carcinoma progression. These alterations are characterized by global genomic DNA hypomethylation leading to genomic instability and oncogene activation concomitantly to an increase of CpG island promoter hypermethylation-mediated silencing of tumor suppressor genes. These changes are accompanied by an increase of aberrant histone modification profiles and miRNA signatures reinforcing oncogenic activation and tumor suppressor loss associated with CRC progression. Consequently, epigenetic alterations represent promising targets for CRC prevention. Early epigenetic aberrations represent interesting targets for primary prevention, especially through chemoprevention by dietary epigenetic modulators, as well as for secondary prevention as early biomarkers of CRC initiation. Modifications occurring at later stages may be targeted by chemotherapeutic interventions as well as chemopreventive agents to limit or block disease progression (secondary and tertiary prevention activities)