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Objective: Cancer metastasis remains the primary cause of cancer-related death worldwide. In a previous study, we found that levels of BTB/POZ domain-containing protein KCTD12 are lower in metastatic melanoma cells than in parental melanoma cells. The purpose of this study was to identify the roles of KCTD12 in cancer metastasis., Methods: The Cancer Genome Atlas (TCGA) datasets were used to evaluate the relationship between KCTD12 and skin cutaneous melanoma (SKCM) prognosis. The effects of endogenous KCTD12 on biological behaviors were examined using the MTT assay. The impacts of KCTD12 on melanoma stemness were explored using spheroid formation assay. KCTD12 knockout A375 cells were generated to confirm the inhibitory effect of KCTD12 on CD271, and a mouse metastatic model was used to determine the impact of KCTD12 on melanoma metastasis in vivo ., Results: KCTD12 levels were lower in lung metastatic cells than in paired parental melanoma cells, and low KCTD12 expression indicated a poor prognosis in SKCM. Cancer metastasis-related capacities were higher in lung metastatic cells than in parental melanoma cells. Moreover, KCTD12 knockdown enhanced tumor growth and metastasis both in vitro and in vivo . Mechanistically, the interaction between KCTD12 and CD271 might be responsible for the stemness transformation after KCTD12 knockdown., Conclusions: This study identifies for the first time the role of the interaction between KCTD12 and CD271 in inducing melanoma cell stemness transformation. Moreover, KCTD12 repression enhances melanoma cell growth, adhesion, migration and invasion., (Copyright 2019 Cancer Biology & Medicine.)