WD repeat and SOCS box containing protein (WSB) molecules have important roles in tumorigenesis. WSB1 is dysfunctional in many malignancies. However, the effects of WSB2 in tumors, including melanoma, have not been reported. Here, we investigated the effects of WSB2 in melanoma cell proliferation, cycle progression, and migration, and the underlying mechanisms.First, WSB2 expression levels and their association with clinicopathological features were evaluated in human melanoma tissue samples. Then, WSB2 was knocked down, using specific shRNA, in melanoma A375 and G361 cells. Proliferation, cycle progression, and migration of A375 and G361 cells were evaluated by 3-(4,5-diethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-etrazolium, inner salt (MTS), colony formation, 5-ethynyl-2'-deoxyuridine (EdU), cycle, and transwell assays. The effects of WSB2 knockdown on melanoma in vivo were determined using a xenograft mouse model. To investigate the underlying mechanisms, levels of c-Myc, β-catenin, phosphorylated retinoblastoma (p-Rb), cyclin-dependent kinase 4 (CDK4), and Cyclin D3 proteins were determined by western blotting in melanoma A375 cells with WSB2 knocked down. Furthermore, β-catenin agonism, SKL2001, was used to evaluate the mechanisms by which knockdown of WSB2 regulated cell proliferation.WSB2 levels were high and they were associated with clinicopathological features in patients with melanoma. shRNA-mediated knockdown of WSB2 could inhibit proliferation, both in vivo and in vitro. Cycle progression and migration of A375 and G361 cells were also significantly inhibited by WSB2 knockdown. Moreover, down-regulation of WSB2 decreased the levels of c-Myc, β-catenin, p-Rb, Cyclin-dependent kinase 4 (CDK4), and Cyclin D3 in melanoma G361 cells with WSB2 knocked down. Moreover, SKL2001 could effectively rescue WSB2 knockdown-mediated inhibition of cell proliferation in melanoma.This is the first report to demonstrate the effects of WSB2 on melanoma cell function. WSB2 has potential to become a new therapeutic target in patients with melanoma.Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.