Epigenetic Control of Estrogen Receptor Expression and Tumor Suppressor Genes Is Modulated by Bioactive Food Compounds

Abstract

Background: The tumor suppressor genes p15^INK4b and p16^INK4a as well as the estrogen receptor-α (ESR1) gene are abnormally methylated and expressed in colon cancer. The cancer-preventative abilities of several bioactive food components have been linked to their estrogenic and epigenetic activities. Methods: The effect of folic acid, zebularine, resveratrol, genistein and epigallocatechin-3-gallate (EGCG) on tumor cell growth, promoter methylation of ESR1, p15^INK4b and p16^INK4a and gene expression of ESR1 and ESR2 was analyzed in Caco-2 cells. Gene expression was measured using real-time PCR, and promoter CpG methylation was assessed using bisulfite conversion and methylation-specific PCR. Results: After exposure to a high concentration of folic acid (20 µmol/l), enhanced cancer cell growth and concomitant increased methylation of the ESR1 (3.6-fold), p16^INK4a and p15^INK4b promoters was observed. A lower concentration of folic acid (2 µmol/l) decreased cell growth. The phytoestrogens genistein and resveratrol enhanced expression of ESR1 (genistein 200 µmol/l: 2.1-fold; resveratrol 50 µmol/l: 6.3-fold) and ESR2 (2.6- and 3.6-fold, respectively). Genistein and resveratrol treatment increased promoter methylation of ESR1 (genistein 200 µmol/l: 2.9-fold; resveratrol 50 µmol/l: 1.4-fold). For p16^INK4a, increased methylation was found after exposure to 10 µmol/l resveratrol, but for p15^INK4b, decreased methylation was found. Both components showed growth-inhibitory activities. For EGCG, growth inhibition at 100 µmol/l and suppressed promoter methylation of tumor suppressor genes (p16^INK4a: 0.9-fold; p15^INK4b: 0.6-fold) was seen. Conclusions: Our results show that these food compounds regulate ESR and tumor suppressor gene expression by multiple mechanisms including epigenetic processes. An improved understanding of these epigenetic effects could therefore support specific dietary concepts of epigenetic cancer prevention and intervention.

Targeting DNA Methylation with Green Tea Catechins

“…Reactivation of some methylation-silenced genes by EGCG has also been demonstrated in human colon cancer HT-29 cells, esophageal cancer KYSE 150 cells and prostate cancer PC3 cells [26,27]. Berner et al [31] have shown that EGCG treatment suppressed promoter methylation of tumor suppressor genes p15 INK4b and p16 INK4a in Caco2 cells [31]. Gao et al [32] have demonstrated that EGCG reverses promoter methylation of tumor suppressor WIF-1 and restores WIF-1 expression in H460 and A549 lung cancer cells [32].…”

Phytochemical Indicaxanthin Inhibits Colon Cancer Cell Growth and Affects the DNA Methylation Status by Influencing Epigenetically Modifying Enzyme Expression and Activity

“…The cancer-preventive abilities of several bioactive food components, including resveratrol, genistein, and EGCG, have been linked also to their ability to regulate tumor suppressor gene expression by epigenetic processes [44]. Our data showed that Ind altered global DNA methylation and induced the demethylation of specific gene promoters, with effects depending on the specific cell line investigated, indicating different sensitivities of different cell lines to the phytochemical.…”

Epigenetic Mechanisms of Colon Cancer Prevention: What Can Nutrition Do?

“…By decreasing DNA methylation and elevating histone acetylation, EGCG treatment induced the reexpression of silenced tumor suppressor genes, p16 and p21, in human skin cancer cells (Nandakumar et al 2011 ). In colon cancer cells, EGCG restored the expression of tumor suppressive p15 and p16 by decreasing their promoter methylation, and repressed colon cancer cell proliferation (Berner et al 2010 ). In addition to regulating DNMTs and causing direct changes in DNA methylation, EGCG has been reported to impact the level of S -adenosylmethionine (SAM), the universal methyl donor, thereby indirectly mediating DNA methylation (Park et al 2012 ).…”