In cancer, genetic mutations have long been considered to be the only driver of neoplasia. However, there is increasing evidence that epigenetic alterations could also play a major role in carcinogenesis and cancer. A number of experimental and epidemiologic studies have shown that many classes of dietary phytochemicals possess cancer-preventive and epigenetic-modifying properties. The report by Derry and colleagues in this issue of the journal shows that grape seed extract (GSE) prevents azoxymethane (AOM)-induced colon colitis via epigenetic microRNA (miRNA) regulation. Although the precise mechanism underlying the control of miRNA expression is not well understood currently, epigenetic changes could play a major role. This report, along with increasing evidence showing the impact of dietary phytochemicals on epigenetic activities, offers new perspectives on miRNA and epigenetic regulation in cancer prevention. Cancer Prev Res; 6(7); 622–4. ©2013 AACR.

See related article by Derry et al., p. 625

In cancer, genetic mutations have long been considered to be the only driver of neoplasia (1). However, there is increasing evidence that epigenetic alterations, defined as changes in the regulation of the expression of gene activity without alteration of genetic structure, could also play a major role in carcinogenesis and cancer (2). Unlike genetic alterations, for instance, chemicals or drugs could reverse a decrease in gene expression due to epigenetic silencing via aberrant promoter hypermethylation. Therefore, small molecules targeting enzymes responsible for DNA methylation and histone modifications could potentially be important for cancer prevention and therapy. In this context, inhibitors of DNA methyltransferases (DNMT) and histone deacetylases (HDAC) have been approved for cancer treatment by the U.S. Food and Drug Administration and proven to have therapeutic potency against a number of malignancies (3). Many classes of dietary phytochemicals have been shown to possess cancer-preventive properties through studies in in vitro and in vivo animal models and findings from numerous epidemiologic studies (4, 5). Surprisingly, these dietary cancer-preventive agents have also been found to regulate epigenetic activities (6–8). For instance, green tea polyphenol (−)-epigallocatechin-3-gallate inhibits DNMT and reactivates methylation-silenced genes in cancer cell lines (9), whereas sulforaphane and 3, 3′-diindolylmethane from cruciferous vegetables have been reported to inhibit HDACs activities (10). Curcumin from turmeric and resveratrol from red grapes have also been reported to elicit epigenetic-modifying activities, among others (11, 12). Hence, epigenetic modifications seem to play an important role in cancer prevention such that they can be inhibited by dietary cancer-preventive phytochemicals.

Grape seed extract (GSE) has been extensively investigated for the prevention and treatment of cancers in in vitro and in vivo preclinical models (13–15). In this issue of the journal, Derry and colleagues report the efficacy of GSE against azoxymethane (AOM)-induced colon tumorigenesis in A/J mice (16). Results from their study show that dietary supplement of GSE dramatically decreases colon tumor incidence and overall tumor size. Biomarker examination shows antiproliferation and proapoptosis effects of GSE on colon tumor tissues. Interestingly, GSE strongly modulates microRNA (miRNA) expression profiles and miRNA-processing machinery associated with alterations in NF-κB, β-catenin, and mitogen-activated protein kinase signaling. Immunohistochemistry analyses show downregulation of inflammatory signaling pathways including NF-κB activation and its downstream targets COX-2, iNOS, and VEGF, decreased β-catenin signaling and its target gene C-myc, and a reduction in phosphorylated extracellular signal-regulated kinase 1/2 levels corroborating miRNA expression profiles. Derry and colleagues suggest that GSE exerts its efficacy against colon tumorigenesis by targeting inflammation, proliferation, and apoptosis possibly via modulation of miRNA expression.

miRNAs are endogenous small noncoding RNA molecules that can control gene expression at both transcriptional and posttranscriptional level. miRNAs bind to their target mRNA in either complete or incomplete complementary fashion, thus they downregulate the stability and/or translation of their target mRNAs (17). miRNAs have been shown to be involved not only in normal tissue differentiation and development (18) but also in carcinogenesis. For instance, Iorio and colleagues reported that miR-21 is aberrantly upregulated in human breast cancers, serving as an antiapoptosis factor (19). Attenuated expression of miR-let7 was reported in human lung cancers, and forced expression of let-7 in A549 lung adenocarcinoma cell line inhibited cell growth (20). More recently, cellular and molecular studies show that miRNAs affect inflammation and cytokine signaling (21, 22), and relatedly, alteration of miRNAs expression by dietary compounds has been shown to be associated with their cancer-preventive and therapeutic benefits (23, 24). Before the report by Derry and colleagues in this issue, regulation of miRNA expression by GSE has been reported in human hepatocellular carcinoma HepG2 cell line (25). Meanwhile, Gao and colleagues reported dysregulation of immune/inflammation-related miRNAs in AOM–dextran sulfate sodium (DSS)–induced colitis-associated colorectal cancer model (26). The current work of Derry and colleagues links the alteration of miRNA expression and those previously identified molecular targets, indicating that a potential epigenetic/miRNA mechanism could exist for the cancer chemopreventive efficacy of GSE.

Although increasing evidence shows the importance of miRNA in cancer initiation and development, the mechanism of miRNA regulation and targeting is still not well understood. Many miRNAs are located in the introns of protein-coding genes (27). As reviewed by You and Jones (2), epigenetic mechanisms including DNA methylation and histone modifications can control the expression of many protein-coding genes, and it is possible that epigenetics could play a critical role in miRNA expression control. A recent study by Wilting and colleagues (28) shows an increase in CpG methylation of miR-149, -203, and -375 during cervical carcinogenesis, whereas expression of these epigenetically silenced miRNAs was restored upon treatment with a potent DNMT inhibitor 5-aza-2′-deoxycytidine. Similarly, inhibition of HDACs leads to a rapid change in miRNA expression profile in human breast cancer cell line SKBr3 (29), while recent studies show the importance of histone methyltransferases and acetyl-histone recognition proteins in miRNA regulation in aggressive B-cell lymphomas (30, 31). As discussed above, many dietary cancer chemopreventive phytochemicals from our daily-consumed fruits and vegetables have been reported to exhibit epigenetic modification activities. With respect to GSE, Vaid and colleagues reported that GSE treatment decreased the expression and activity of DNMT, caused downregulation of global DNA methylation level, and resulted in reactivation of silenced tumor suppressor genes, such as RASSF1A, p16INK4a(CDKN2A), and Cip1/p21(CDKN1A) in human squamous cell carcinoma A431 and SCC13 cell lines (32). Together, these findings may provide some insights into the epigenetic regulatory mechanism by GSE from 2 possible scenarios: GSE may turn on the tumor suppressor genes that are aberrantly silenced by epigenetic mechanism via CpG demethylation and histone modifications, and on the other side of the coin, GSE may reactivate miRNAs controlling tumor suppressor genes resulting in downregulation of target oncogenic mRNAs. Further studies would be needed to interrogate the connectivity between epigenetic changes and alteration of miRNA expression profiles by GSE and other cancer-preventive dietary phytochemicals in in vitro and in vivo cancer models.

In conclusion, the findings of Derry and colleagues and others, epigenetic modifications by dietary phytochemicals in cancer prevention, provide new potential insights into cancer-preventive mechanisms of GSE and other dietary phytochemicals. It is highly conceivable that epigenetically controlled chromatin remodeling such as CpG methylation, histone modifications as well as miRNA that drive various stages of carcinogenesis could be intervened or interrupted by dietary cancer-preventive phytochemicals (33). Uncovering these potential epigenetic molecular targets by phytochemicals will certainly advance our basic understanding of carcinogenesis and phytochemical–cancer relationships that can ultimately translate to chemopreventive or therapeutic strategies.

No potential conflicts of interest were disclosed.

Conception and design: A.-N.T. Kong, Z.-Y. Su

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): A.-N.T. Kong

Writing, review, and/or revision of the manuscript: A.-N.T. Kong, C. Zhang, Z.-Y. Su

Study supervision: A.-N.T. Kong

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Supplementary data