Colorectal cancer (CRC) is the third most-diagnosed and second most-deadly cancer worldwide. Thanks to federally funded efforts to profile DNA methylation abnormalities in colon and other cancer types, we know that most cancer types, including CRC, exhibit aberrant DNA methylation signatures compared to normal tissue, but much remains to be uncovered regarding how DNA methylation may facilitate tumorigenesis and be therapeutically targeted for the treatment or prevention of disease. In this dissertation, we add depth to our understanding of the role of DNA methylation and Dnmt1 in intestinal tumorigenesis through the following four key areas of investigation: 1) understanding the role of pre-existing DNA methylation in tumor predisposition, 2) investigating mechanisms by which DNA hypermethylation may arise in cells, 3) determining the impact of Dnmt1 manipulation on intestinal tumorigenesis, and 4) developing model systems and tools to identify and validate epigenetic drivers of tumorigenesis.

Through these investigations, we have uncovered a previously unappreciated role for the pre-existing DNA methylation state of normal intestinal cells in their predisposition to becoming tumor cells. Even the strong genetic driver event of loss of Apc function appears to require other epigenetic gatekeeper events to enable tumor formation in mice. We found in two different models of Dnmt1 repression that its repression is a potent suppressor of tumorigenesis, which appears to be accomplished through complex rewiring of proliferative, metabolic, and immune signaling. On the other hand, we found that overexpression of Dnmt1 exacerbates tumorigenesis in Apc^Min/+ mice, likely in part through epigenetic misregulation of miRNAs. We expect these findings will be informative for clinical application of DNMT1 inhibitors in cancer prevention and therapy as well as for the development of targeted epigenetic therapies in the coming years.