Epigenetic re-expression of important genes silenced in the pathway of carcinogenesis represents an exciting new area for cancer chemoprevention. The long-range goal of this project is to identify naturally occurring phytochemicals that reverse the inhibition of master cell signaling pathways. One such master switch is the retinoid X receptor (RXR). That RXR is proposed to also be involved in Apc-independent degradation of beta- catenin pivotally places it at the center of crosstalk of cell signaling molecules, often corrupted in colon tumorigenesis. Polyphenols from green tea have widespread cancer chemopreventive activity. At least one of the green tea catechins, epigallocatechin gallate (EGCG) has been reported to restore activity of silenced growth regulatory genes in squamous cell cancers. Our preliminary data suggest that green tea modulates the hypermethylation of RXR alpha gene promoter, and inhibits intestinal tumorigenesis in the azoxymethane- treated ApcMIN/+ mouse. We hypothesize that RXRa is lost early in colon cancer due to gene and that green tea polyphenols restore this activity by inhibition of DMNTs and HDACs, providing a novel mechanism of chemoprevention for colon cancer.
Our aims are:
In Specific Aim 1, in colon cancer cell lines and in human colorectal tumors establish that loss of RXRa is an early event in colon cancer.
In Specific Aim 2, in colon cancer cell lines, determine if EGCG is responsible for changes in HDACs that associate with the promoter region of RXRa, RAR?, hMLH1, p14arf, and p16INK4a and compare this activity with other known inhibitors of HDACs.
In Specific Aim 3, we will determine if inhibition of DNA methyltransferases (DNMTs) is an important component of epigenetic regulation of RXRa activity and other methylated target genes in colon cancer cell lines.
In Specific Aim 4 we will examine the chemopreventive effects of green tea/EGCG intervention on RXRa gene dosage in RXRa+/- mice with the colon carcinogen, AOM. We will also examine the effects of green tea/EGCG intervention in intestinal tumorigenesis in ApcMIN/+ RXR+/- and ApcMIN/+ RXR+/+ bigenic mice. The working hypothesis for this aim is that loss of RXRa will augment colon carcinogenesis in RXRa deficient mice. We also explore the effects of GT and EGCG intervention on the reactivation of silenced RXRa in the AOM- treated ApcMIN/+ RXR+/- bigenic mice.
Silencing of critical regulatory genes by epigenetic mechanisms may play a critical role in colon cancer. We hypothesize that green tea polyphenols suppress DNA methyltransferases and histone acetylase activity. This, in turn, may allow re-expression of growth regulatory genes and provide a means of cancer control for this disease. Because RXRa loss involves impairment of regulatory gene networks, the impact of green tea reversal of this transcription factor's loss is significant.
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