We identified aberrant CTCF binding lead to a 3D chromosomal interactional driver in NTS locus that accelerates tumorigenesis of uveal melanoma. Both enhancer deletion and abolishing CTCF binding lead to the loss of chromosomal looping and triggered therapeutic efficacy in inhibiting tumorigenesis. Our study shed light on a functional chromosomal architecture induced enhancer hijacking, thereby provide novel concept of 3D-chromosomal conformation exploration. Overall design: We performed microarray in 2 types of ocular melanoma cells with or without decoyed CTCF