Reduction in promotor methylation utilizing EGCG (epigallocatechin-3-gallate) restores RXRα expression in human colon cancer cells

Abstract

Silencing of regulatory genes through hypermethylation of CpG islands is an important mechanism in tumorigenesis. In colon cancer, RXRα, an important dimerization partner with other nuclear transcription factors, is silenced through this mechanism. We previously found that colon tumors in Apc Min/+ mice had diminished levels of RXRα protein and expression levels of this gene were restored by treatment with a green tea intervention, due to reduced promoter methylation of RXRα. We hypothesized that CIMP+ cell lines, which epigenetically silence key regulatory genes would also evidence silencing of RXRα and EGCG treatment would restore its expression. We indeed found EGCG to restore RXRα activity levels in the human cell lines, in a dose dependent manner and reduced RXRα promoter methylation. EGCG induced methylation changes in several other colon cancer related genes but did not cause a decrease in global methylation. Numerous epidemiological reports have shown the benefits of green tea consumption in reducing colon cancer risk but to date no studies have shown that the risk reduction may be related to the epigenetic restoration by tea polyphenols. Our results show that EGCG modulates the reversal of gene silencing involved in colon carcinogenesis providing a possible avenue for colon cancer prevention and treatment.

Epigallocatechin gallate in combination with eugenol or amarogentin shows synergistic chemotherapeutic potential in cervical cancer cell line

“…It was evident that the combinatorial treatment could highly modulate the genes associated with G1/S cell cycle checkpoint than (Figure 8). The reduced expression of DNMT1 by EGCG has been reported by different studies (Henning, Wang, Carpenter, & Heber, 2013;Morris et al, 2016), but no such phenomenon has been reported in case eugenol and amarogentin.…”

Dietary antioxidants remodel DNA methylation patterns in chronic disease

“…For instance, RARβ, cadherin 1 (CDH1), and death-associated protein kinase-1 (DAPK1) were demethylated and re-activated in EGCG-treated HeLa cells . Similar changes in methylation and expression of retinoic X receptor α (RXRα) in colon cancer (Morris et al, 2016), p16(INK4a), RARβ, O(6)methylguanine methyltransferase (MGMT) and human mutL homologue 1 (hMLH1) in oesophageal cancer cells (Fang et al, 2003), and RECK in oral squamous cell carcinoma (Kato et al, 2008) were observed.…”

“…Resveratrol has been reported to regulate one of the major antioxidant pathways, namely, the Nrf2 pathway through an epigenetic mechanism(s) (Singh et al, 2014; Figure 4 and Table 1). In female rats 5.6 | Epigallocatechin gallate 5.6.1 | Mechanisms behind changes in DNA methylation in response to EGCG Many studies conducted in cancer models have reported EGCGmediated transcriptional activation of methylation-silenced tumour suppressor genes through a decrease in promoter methylation (Fang et al, 2003;Kato et al, 2008;Khan et al, 2015;Lee, Shim, & Zhu, 2005;Morris et al, 2016). For instance, RARβ, cadherin 1 (CDH1), and death-associated protein kinase-1 (DAPK1) were demethylated and re-activated in EGCG-treated HeLa cells .…”

The Effects of Metformin on Thyroid Function among Patients with Subclinical Hypothyroidism and Coexisting Metabolic Syndrome

“…In general, at the molecular level, metformin may generate its effects via adenosine monophosphate-activated protein kinas (AMPK) and subsequent inhibition of mammalian targets of rapamycin (mTOR), which is involved in supplying of cellular energy and regulation of TRH/TSH pathway. 8,9,29,30 In other study Krysiak et al indicated the proper role of gender on metformin effects in hypothalamic-pituitary-thyroid axis activity. 31 Furthermore, previous studies showed that the levels of TSH in obese patients were slightly more than in normal population.…”

“…6,7 Furthermore, it has been reported that metformin decelerates tumor growth in various types of cancers including thyroid cancer. 8,9 A meta-analysis research evaluating the alteration of TSH levels in patients treated with metformin, showed that TSH levels decrease at both overt and subclinical hypothyroidism groups with no changes in euthyroid subjects. 10 In addition, Karimifar et al in a double-blind placebocontrol clinical trial, revealed that metformin treatment causes a decrease in the levels of serum TSH in patients with TSH level higher than 2.5 mIU/l.…”