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 ApcMin/+ 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.
Highlights
Genetic mutations have long been a central theme in the causality of cancer
To further explore the possibility that epigallocatechin gallate (EGCG) could reverse RXRα loss of expression in human colon cancer, we tested the ability of EGCG to suppress proliferation in several human colon cancer cell lines, chosen for differences in their molecular phenotypes
To further explore whether EGCG relieved promoter methylation in other target genes reported to be epigenetically silenced in human colon cancer, we examined the degree of methylation in the promoters of Apc, p14arf, p16ink4a and hMLH1 genes in HCT116 and HT29 cell lines
Summary
Genetic mutations have long been a central theme in the causality of cancer. Recently, Hanahan and Weinberg [1] expanded their previous tenets on the origins of human cancer to include epigenetic events in the pathway of carcinogenesis. Across the paradigm of cancer, recent data suggest that epigenetic events are of central importance in regulation of tumor formation and progression, possibly creating a new avenue for prevention and treatment [1,2,3]. Regulation of the epigenome is under the control of DNA methyltransferases (DNMTs), histone deacetylases (HDACs), histone acetyltransferases (HATs) and associated modifier proteins [2, 4, 5]. Compounds regulating these proteins or altering their function is an emerging field for drug development. Some pharmacologic inhibitors such as 5-Aza-2’deoxycytidine (5aza-dc) and suberoylanilide hydroxamic acid (SAHA) have entered clinical testing, but off-target toxicity has limited its progress [6]
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