Somatic c.4467delA mutations in colorectal cancers control histone methylation and tumor growth.

The chromatin modifier is inactivated by mutation in several forms of cancer and is a putative tumor suppressor gene. Frameshift mutations in the C-terminal region of , affecting (A)8 or (A)9 repeats within exon 8, are found in one third of colorectal cancers with microsatellite instability, but the contribution of these mutations to colorectal tumorigenesis is unknown. To model somatic mutations in microsatellite unstable tumors, we devised a general approach to perform genome editing while stabilizing the mutated nucleotide repeat. We then engineered isogenic cell systems where the c.4467delA mutation in human HCT116 colorectal cancer cells was corrected to wild-type by genome editing. Restored increased global histone 3 lysine 9 dimethylation and reduced migration, anchorage-independent growth and tumor growth . Gene set enrichment analysis revealed regulation of several hallmark cancer pathways, particularly of epithelial-to-mesenchymal transition (EMT), with VIM being the most significantly regulated gene. These observations provide direct evidence that c.4467delA is a driver mutation in colorectal cancer and confirms as a cancer gene, pointing to regulation of EMT as a central aspect of its tumor suppressive action.