In the present review, we summarized the mutations of epigenetic regulators, including ARID1A, SMARCA2, SMARCA4, KDM6A, KMT2C, KMT2D, and BRD4 in GI cancers—in particular, pancreatic cancer—and found these regulators to be frequently mutated. This evidence concerns the gene KDM6A and pancreatic neoplasm.