Naked cuticle homolog2 (NKD2) is located in chromosome 5p15.3, which is a frequent loss of heterozygosity in human colorectal and gastric cancers. Naked2 (NKD2), one member of the Naked family, has been shown to negatively regulate the Wnt/β-catenin signaling pathway. It has been recognized that NKD2 plays a vital role in cell homeostasis and the prevention of tumorigenesis. NKD2 inhibits tumor growth and metastasis in OS by suppressing Wnt signaling. Naked cuticle homolog 2 (NKD2) was found to be frequently methylated in human breast and gastric cancers. NKD2 is frequently methylated in human esophageal cancer, and the expression of NKD2 is regulated by promoter region methylation. NKD2 suppresses esophageal cancer progression by inhibiting Wnt signaling both in vitro and in vivo.