Skeletrophin (mindbomb homolog 2 (MIB2)) is a RING (Really Interesting New Gene) finger-dependent ubiquitin ligase, which targets the intracellular region of Notch ligands. A previous immunohistochemical study demonstrated that skeletrophin was downregulated in many melanomas. In the present study, we have identified a promoter region of skeletrophin on a CpG island and detected aberrant methylation of this region in six of 31 invasive melanomas, but in none of 25 benign nevi or five non-invasive superficial spreading melanomas. Subsequently, we found that a zinc-finger transcriptional factor Snail, which is overexpressed in many melanoma cells, repressed the skeletrophin promoter activity via an E-box-related element and was involved in downregulation of skeletrophin. An activator protein-2, which has a tumor suppressor-like role in melanoma, increased skeletrophin expression. Interestingly, exogenously expressed skeletrophin reduced melanoma cell invasion in vitro and in vivo. Colony formation in soft agar was also reduced in a RING motif-dependent manner, without affecting cell growth. We also found that skeletrophin downregulated transcription of the Met oncogene, which encodes the hepatocyte growth factor receptor and plays a role in the determination of the invasive phenotype of many malignant tumors. Finally, exogenously expressed skeletrophin, but not its RING mutant, increased transcription of Hes1 gene, a downstream effector of Notch pathway in melanoma cells. The present findings indicate that skeletrophin might be a novel suppressor factor for melanoma invasion.