Modulation of gene methylation by genistein or lycopene in breast cancer cells

Abstract

Dietary agents with chemopreventive potential, including soy-derived genistein and tomato-derived lycopene, have been shown to alter gene expression in ways that can either promote or potentially inhibit the carcinogenic processes. To begin to explore the mechanisms by which these agents may be acting we have examined the DNA methylation modulating capacity of genistein or lycopene for several genes relevant to breast cancer in the breast cancer cell lines MCF-7 and MDA-MB-468, as well as in immortalized but noncancer fibrocystic MCF10A breast cells. We find using methylation specific PCR (MSP) that a low, nontoxic concentration of genistein (3.125 lM, resupplemented every 48 hr for 1 week) or a single dose of lycopene (2 lM) partially demethylates the promoter of the GSTP1 tumor suppressor gene in MDA-MB-468 cells. RT-PCR studies confirm a lack of GSTP1 expression in untreated MDA-MB-468, with restoration of GSTP1 expression after genistein or lycopene treatment. The RARb2 gene however, was not demethylated by genistein or lycopene in either of these breast cancer cell lines. But, lycopene (2 lM, once per week for 2 weeks) did induce demethylation of RARb2 and the HIN-1 genes in the noncancer MCF10A fibrocystic breast cells. These data show for the first time that the tomato carotenoid lycopene has direct DNA demethylating activity. In summary, both genistein and lycopene, at very low, dietarily relevant concentrations can potentially mitigate tumorigenic processes via promoter methylation modulation of gene expression. Environ. Mol. Mutagen. 49:36-45, 2008.

Plant Phytochemicals as Epigenetic Modulators: Role in Cancer Chemoprevention

“…Reactivation of RARβ by the reversal of DNA hypermethylation by genistein was also observed in human prostate cancer LNCaP and PC3 cells (65). Treatment of human breast cancer MDA-MB-468 cells with low concentrations of genistein restored the expression of GSTP1 gene by partially demethylating its promoter (66). In human prostate cancer PC-3, DU-145, and LNCaP cell lines, in which promoters of GSTP1 and EPHB2 are strongly methylated, treatment with soy isoflavones genistein and daidzein caused demethylation of these promoters and increased protein expression (67).…”

“…Demethylation of RARβ2 and HIN-1 genes in immortalized non-tumorigenic MCF10A fibrocystic breast cells however was observed after 2 weeks of lycopene treatment. The study shows that lycopene has direct DNA demethylating activity (66).…”

Genistein Derivatization – From a Dietary Supplement to a Pharmaceutical Agent

“…The ability of genistein to change the methylation status was observed in several other studies. Genistein was shown to partially demethylate the promoter of the GSTP1 tumor suppressor gene in MDA-MB-468 breast cancer line (King-Batoon et al, 2008). Another study shown the change of methylation status in mice prenatally exposed to genistein (Vanhees et al, 2011).…”

Globalisation and the Epigenetic Landscape

“…While 1-carbon metabolism and folate availability have, to date, been a major focus of attention, it is increasingly apparent that altered DNA methylation is not simply an issue of the bioavailability of methyl groups. For example, the isoflavone, genistein, has profound effects on DNA methylation but has no involvement in 1-carbon metabolism (King-Batoon et al, 2008).…”