Reduction of DNA methylation suppresses colon carcinogenesis through induction of tumor cell differentiation

In this study, we analyzed global gene expressions of colon tumors from DNA hypomethylated and the control mice. We found that DNA hypomethylated tumors express significantly higher levels of intestinal differentiation-related genes when compared with the control tumors. These results suggest that DNA methylation may play a role in the maintenance of undifferentiated state of colon tumor cells. Two different Dnmt1 mutant alleles were used in this study; hypomorphic Dnmt1chip allele and conventional KO Dnmt1c allele, which described previously. Previous studies indicated that Dnmt1chip/c mice have reduced DNA methylation contents at pericentromeric satellite repeats, while Dnmt1chip/+ mice have the same levels of genomic methylation as wildtype mice. Experimental mice in an isogenic F1 hybrid background were obtained by breeding Dnmt1c/+; ApcMin/+ mouse in the C57BL/6 background with Dnmt1chip/chip; Apc+/+ mouse in the 129Sv4 background. Six-week-old DNA hypomethylated (Dnmt1chip/c; ApcMin/+) and the control (Dnmt1chip/+; ApcMin/+) mice were fed with 2% (w/v) dextran sodium sulfate (DSS), a potent promoter for colon carcinogenesis. At 20 weeks of age, colon tumors were harvested from both cohorts (n=3 for both DNA hypomethylated tumors and the control tumors) and analyzed for their gene expressions.