Epigenetic Regulation of Apoptosis and Cell Cycle Regulatory Genes in Human Colon Carcinoma Cells.

Abstract

5-Fluorouracil (5-FU) is the standard chemotherapy for certain high risk stage 2 and all stage 3 and 4 human colorectal cancer patients. However, patients often develop chemoresistance to 5-FU. We have identified verticillin A from Verticillium-infected wild mushrooms as a potent anti-cancer agent that effectively suppresses 5-FU-resistant human colon cancer cells. Interestingly, a sublethal dose of verticillin A also acts as a potent sensitizer that overcomes human colon carcinoma cell resistance to FasL- and TRAIL-induced apoptosis. To identify verticillin A-regulated genes, we performed a genome-wide gene expression analysis and identified 1287 genes whose expression levels were either up- or down-regulated 1.5 fold. Forty-six of these genes have known function in regulation of apoptosis, and ninety genes have function in cell cycle regulation. Our recent study has identified verticillin A as a selective histone methyltransferase inhibitor. These identified genes are thus potential molecular targets for epigenetic-based therapy to overcome human colon cancer 5-FU resistance. The entire dataset is deposited in the NIH GEO database; accession number GSE51262.