Much of the global cancer burden is associated with longstanding inflammation accompanied by release of DNA-damaging reactive oxygen and nitrogen species. Here, we report that the Mbd4 DNA glycosylase is protective in the azoxymethane/dextran sodium sulfate (AOM/DSS) mouse model of inflammation-driven colon cancer. Mbd4 excises T and U from T:G and U:G mismatches caused by deamination of 5-methylcytosine and cytosine. Since the rate of deamination is higher in inflamed tissues, we investigated the role of Mbd4 in inflammation-driven tumorigenesis. In the AOM/DSS assay, Mbd4-/- mice displayed more severe clinical symptoms, decreased survival, and a greater tumor burden than wild-type (WT) controls. The increased tumor burden in Mbd4-/- mice did not arise from impairment of AOM-induced apoptosis in the intestinal crypt. Histopathological analysis indicated that the colonic epithelium of Mbd4-/- mice is more vulnerable than WT to DSS-induced tissue damage. We investigated the role of the Mbd4-/- immune system in AOM/DSS-mediated carcinogenesis by repeating the assay on WT and Mbd4-/- mice transplanted with WT bone marrow. Mbd4-/- mice with WT bone marrow behaved similarly to Mbd4-/- mice. Together, our results indicate that the colonic epithelium of Mbd4-/- mice is more vulnerable to DSS-induced injury, which exacerbates inflammation-driven tissue injury and cancer.
Keywords: AOM/DSS; Mbd4; colon cancer; inflammation; ulcerative colitis.