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.