Abstract A194: Epigenetic modification of RXRα in human colon carcinomas by the green tea polyphenol, EGCG

Abstract

Abstract Silencing of regulatory genes through hypermethylation of CpG islands is an important mechanism in tumorigenesis of numerous cancers. In colon cancer, one such gene which undergoes this type of silencing is Retinoid X Receptor alpha (RXRα) an important dimerization partner with other nuclear transcription factors. Previous studies have shown that ApcMin/+ mice treated with the carcinogen azoxymethane (AOM) will develop colonic tumors and when treated with green tea a reduction in tumor numbers was found. AOM treated mice also have reduced RXRα protein levels which is restored by treatment with green tea, reducing the amount of promoter methylation. We examined human colonic tumor microarrays by immunohistochemcial staining and found a marked decrease in RXRα a expression in tumor tissue compared to normal matched tissues, inversely β-Catenin levels increased. To determine how RXRα loss is reversed in human cancers by green tea, we treated HT-29 (methylation insensitive) and HCT116 (methylation sensitive) human colon cancer cell lines with Epigallocatechin gallate (EGCG - major polyphenolic compound in green tea for 48, 72 & 96 hr; 2, 3 & 4 doubling times). We found EGCG to restore RXRα activity levels in HCT116 cells treated with EGCG, in a dose dependant manner. We also found that EGCG treatments reduce the amount of promoter methlyation in 2 CpG island in the RXR promoter in HCT116 cells in a dose dependant manner. Numerous epidemiological reports have shown the benefits of green tea consumption in reducing colon cancer risks but to date no known studies have shown direct genetic effects of green tea on human colon cancer cells. Our results here show that EGCG, a common dietary compound, can modulate the reversal of gene-silencing involved colon carcinogenesis and maybe a possible avenue for colon cancer treatment. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A194.