Wnt/beta-catenin signaling pathway plays an important role in embryogenesis, stem cell maintenance, tumorigenesis and aging. Here, we show that RNA-binding protein, coding region determinant-binding protein (CRD-BP) (a transcriptional target of Wnt signaling pathway), is highly expressed in primary human malignant melanomas and melanoma cell lines with activated Wnt/beta-catenin signaling pathway. Upregulation of CRD-BP is associated with an elevated level of beta-TrCP1 ubiquitin ligase receptor and activation of nuclear transcriptional factors-kappa B (NF-kappaB) signaling. Knockdown of CRD-BP inhibits NF-kappaB activity, induces apoptosis, and suppresses proliferation and tumorigenic properties of melanoma cells.