Luo et al. identified that the CUL4B-DDB1-COP1 complex acts as a functional E3 ligase targeting KDM6A for degradation to promote CRC progression, and KDM6A deletion in intestinal epithelial cells enhances susceptibility to tumorigenesis in a spontaneous mouse CRC model [162]. Here, CUL4B is linked to colorectal carcinoma.