APC coordinates GSK3 phosphorylation of SETD8 to suppress colorectal cancer

Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths. Mutations in the tumor-suppressor APC initiate CRC in part by preventing the glycogen synthase kinase 3 (GSK3) kinase from phosphorylating β-CATENIN, leading to its stabilization and transactivation of mitogenic target genes. While the importance of β-CATENIN phosphorylation by GSK3 is well established, APC regulation of GSK3 activity upon other targets is not understood. Here, we identify the H4K20 methyltransferase SETD8 as a target of APC-coordinated GSK3 phosphorylation in the intestinal epithelium. We find that phosphorylation by GSK3 restrains the oncogenic activity of SETD8, with loss of phosphorylation sensitizing mice to oncogenic insults. Mechanistically, loss of SETD8 phosphorylation in tumors results in a loss of H4K20 monomethylation (H4K20me1) deposition at oncogenic cholesterol biosynthesis and fetal intestinal genes, allowing for their activation in part through gain of YAP accessibility. These results underscore the importance of SETD8 in CRC and represent a novel β-CATENIN-independent oncogenic consequence of APC loss.