Epigenetic and genetic mechanisms contribute to telomerase inhibition by EGCG

Abstract

The ends of human chromosomes are protected from the degradation associated with cell division by 15-20 kb long segments of hexameric repeats of 5'-TTAGGG-3' termed telomeres. In normal cells telomeres lose up to 300 bp of DNA per cell division that ultimately leads to senescence; however, most cancer cells bypass this lifespan restriction through the expression of telomerase. hTERT, the catalytic subunit essential for the proper function of telomerase, has been shown to be expressed in approximately 90% of all cancers. In this study we investigated the hTERT inhibiting effects of (-)-epigallocatechin-3-gallate (EGCG), the major polyphenol found in green tea catechins, in MCF-7 breast cancers cells and HL60 promyelocytic leukemia cells. Exposure to EGCG reduced cellular proliferation and induced apoptosis in both MCF-7 and HL60 cells in vitro, although hTERT mRNA expression was decreased only in MCF-7 cells when treated with EGCG. Furthermore, down-regulation of hTERT gene expression in MCF-7 cells appeared to be largely due to epigenetic alterations. Treatment of MCF-7 cells with EGCG resulted in a time-dependent decrease in hTERT promoter methylation and ablated histone H3 Lys9 acetylation. In conjunction with demethylation, further analysis showed an increase in hTERT repressor E2F-1 binding at the promoter. From these findings, we propose that EGCG is effective in causing cell death in both MCF-7 and HL60 cancer cell lines and may work through different pathways involving both anti-oxidant effects and epigenetic modulation.

Differentiated impact of procyanidins from evening primrose on human breast cancer cells

“…In 2008, over 12 million new cancer cases were diagnosed worldwide, breast cancer being one of the most frequently diagnosed in women, and the one characterized with the highest mortality rate [10]. However, a large body of data exists on the influence of polyphenols of plant origin on breast cancer [11][12][13][14]. For instance, an extract from the fruit of Terminalia chebula Retz.…”

“…(yellow myrobalan or chebulic myrobalan) effectively inhibits the proliferation of murine and human mammary gland cancer cells (S115 and MCF-7, respectively) [11]. Epigallocatechin gallate (EGCG), the main phenolic constituent of green tea whose antiproliferative activity towards cancer cells is the most widely reported among polyphenols, also inhibits the growth of MCF-7 cells [12]. Genistein, a soy isoflavone, was found to cause G2/M cell cycle arrest in MDA-MB-231 and MCF-7 mammary gland cancer cell lines [13].…”

Epigenetic linkage of aging, cancer and nutrition

“…Inhibition of telomerase has also been shown after EGCG treatment. In this study, EGCG downregulated hTERT expression in MCF-7 human breast cancer cells, largely as a result of TERT promoter demethylation and ablated histone H3 Lys9 acetylation (Berletch et al, 2008).…”

Green tea mechanism of action in fighting different types of cancer

“…Furthermore, EGCG (0-100 µM) dose-dependently inhibited OVCAR-3 cell migration. The protein expression levels of MMP-2, but not MMP-9, were dose-dependently decreased following treatment with EGCG (0-100 µM) for 48 h; leading to inhibited OVCAR-3 cell proliferation and migration, potentially mediated via the activation of p38 MAPK and downregulation of the protein expression of MMP-2 .It has been reported that EGCG can induce apoptosis in breast cancer cells, and EGCG can target cancer cells through a variety of mechanisms, including decreasing expression of hTERT, the major catalytic subunit of telomerase (Berletch et al, 2008).…”