Cancer Chemoprevention by Targeting the Epigenome

Abstract

The term "epigenetics" refers to modifications in gene expression caused by heritable, but potentially reversible, changes in DNA methylation and chromatin structure. Given the fact that epigenetic modifications occur early in carcinogenesis and represent potentially initiating events in cancer development, they have been identified as promising new targets for prevention strategies. The present review will give a comprehensive overview of the current literature on chemopreventive agents and their influence on major epigenetic mechanisms, that is DNA methylation, histone acetylation and methylation, and microRNAs, both in vitro and in rodent and human studies, taking into consideration specific mechanisms of action, target sites, concentrations, methods used for analysis, and outcome. Chemopreventive agents with reported mechanisms targeting the epigenome include micronutrients (folate, selenium, retinoic acid, Vit. E), butyrate, polyphenols (from green tea, apples, coffee, and other dietary sources), genistein and soy isoflavones, parthenolide, curcumin, ellagitannin, indol-3-carbinol (I3C) and diindolylmethane (DIM), mahanine, nordihydroguaiaretic acid (NDGA), lycopene, sulfur-containing compounds from Allium and cruciferous vegetables (sulforaphane, phenylethyl isothiocyanate (PEITC), phenylhexyl isothiocyanate (PHI), diallyldisulfide (DADS), allyl mercaptan (AM)), antibiotics (mithramycin A, apicidin), pharmacological agents (celecoxib, DFMO, 5-aza-2'-deoxycytidine and zebularine), compounds affecting sirtuin activity (resveratrol, dihydrocoumarin, cambinol), inhibitors of histone acetyl transferases (anacardic acid, garcinol, ursodeoxycholic acid), and relatively unexplored modulators of histone lysine methylation (chaetocin, polyamine analogues, n-3 polyunsaturated fatty acids). Their effects on global DNA methylation, tumor suppressor genes silenced by promoter methylation, histone modifications, and miRNAs deregulated during carcinogenesis have potential impact on multiple mechanisms relevant for chemoprevention, including signal transduction mediated by nuclear receptors and transcription factors such as NF-κB, cell cycle progression, cellular differentiation, apoptosis induction, senescence and others. In vivo studies that demonstrate the functional relevance of epigenetic mechanisms for chemopreventive efficacy are still limited. Future research will need to identify best strategies for chemopreventive intervention, taking into account the importance of epigenetic mechanisms for gene regulation.

Epigenetic deregulation of miR-29a and miR-1256 by isoflavone contributes to the inhibition of prostate cancer cell growth and invasion

“…9,10 We have previously reported that isoflavone could alter the miRNA expression profiles, leading to the inhibition of cancer cell growth, induction of apoptosis, reversal of epithelial-to-mesenchymal transition (EMT), and enhancement of efficacy of conventional cancer therapeutics. 11,12 In this study, we investigated whether isoflavone could demethylate DNA sequences in the promoter of tumor suppressive miR-29a and other miRNAs and thus affect the expression of their target genes.…”

Inhibition of Tumor Promotion by Parthenolide: Epigenetic Modulation of p21

“…Tumors grew spherically, and their diameters were measured with a hole-mask. Tumor volumes were calculated as (4/3)pr 3 . Animals were sacrificed by cervical dislocation when the tumor diameter reached 25 mm.…”

“…In particular, the promotion phase is a rate-limiting step in the tumorigenesis process (1), is mostly epigenetically regulated, hence, reversible, and is an attractive target for chemoprevention (3). The JB6-cell model is ideal to study tumor promotion and widely used to identify antitumor promotion agents (4).…”

Epigenetic Modifications of Nrf2 by 3,3′-diindolylmethane In Vitro in TRAMP C1 Cell Line and In Vivo TRAMP Prostate Tumors

“…For example, the hypermethylation status in the promoter regions of tumor-suppressing genes has been demonstrated in various cancers recently, such as estrogen receptor α (ESR1), glutathione S-transferase π1 (GSTP1), retinoid acid receptor β2 (RARβ2), and death-associated protein kinase 1 (DAPK1) in breast cancer; ESR1 and RARβ2 in colorectal cancer; GSTP1 and RARβ2 in prostate cancers; and DAPK1 in lung cancers (2,3).…”