Abstract A39: EGCG, a green tea polyphenol, can reverse methylation related silencing of genes in human colon carcinomas

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. Previous studies from our laboratory have shown that ApcMin/+ mice treated with the carcinogen azoxymethane (AOM) will develop colonic tumors but when treated with green tea a reduction in tumor numbers was found. We found that colon tumors had lower expression of RXR protein but expression levels were restored by treatment with green tea. We also found that the degree of promoter methylation of the RXR gene was reduced. To translate these findings to human colon cancer we treated CpG Island Methylator Phenotype sensitive and insensitive (CIMP+ & CIMP-) human colon cancer cell lines with epigallocatechin gallate (EGCG - major polyphenolic compound in green tea). We hypothesized that CIMP+ cell lines which epigenetically silence key regulatory genes would demonstrate silencing of RXRα and that EGCG would restore its expression. To test this we used the following human colon cancer cell lines: HCT116, SW48, HCT15 - CIMP+; HT29, SW480, SW620 - CIMP- and IEC-6 - normal control. We found EGCG to restore RXR activity levels in the CIMP+ lines, in a dose dependent manner (0, 50, 100 & 150 μM EGCG was tested for 48 and 72 hour durations). EGCG also reduced RXRα promoter methylation in one CpG island from a CIMP+ cell line compared to a CIMP-line. We found that EGCG produced 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 some of the risk reduction may be related to the epigenetic regulation of key genes by constituent tea polyphenols. Our results here show that EGCG, a common tea polyphenolic compound, can modulate the reversal of gene-silencing involved colon carcinogenesis and maybe a possible avenue for colon cancer treatment. Supported by USPHS grant CA96694 from the National Cancer Institute. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A39.