Fig. 6: DNA hypomethylation and Wnt pathway cooperatively activate caspase-3 expression to suppress intestinal tumorigenesis.

Working model illustrates how DNA hypomethylation suppresses intestinal tumorigenesis by promoting caspase-3 expression and apoptosis. In Uhrf1^ki/ki mice or Apc^min/+ mice, DNA hypomethylation or activation of Wnt pathway alone is not sufficient to significantly enhance caspase-3 gene expression. However, DNA hypomethylation caused by Uhrf1-TTD-KI mutation can promote caspase-3 transcriptional activation by Wnt canonical and noncanonical pathway-activated transcription factors such as TCF1/2, AP-1, and c-jun and β-catenin, which in turn leads to elevated apoptosis and tumor suppression.