Melanomas are well-known for their altered mRNA expression profiles. Yet, the specific contribution of mRNA binding proteins (mRBPs) to melanoma development remains unclear. Here we identify a cluster of melanoma-enriched genes under the control of CUGBP Elav-like family member 1 (CELF1). CELF1 was discovered with a distinct prognostic value in melanoma after mining the genomic landscape of the 692 known mRBPs across different cancer types. Genome-wide transcriptomic, proteomic, and RNA-immunoprecipitation studies, together with loss-of-function analyses in cell lines, and histopathological evaluation in clinical biopsies, revealed an intricate repertoire of CELF1-RNA interactors with minimal overlap with other malignancies. This systems approach uncovered the oncogene DEK as an unexpected target and downstream effector of CELF1. Importantly, CELF1 and DEK were found to represent early-induced melanoma genes and adverse indicators of overall patient survival. These results underscore novel roles of CELF1 in melanoma, illustrating tumor type-restricted functions of RBPs in cancer.

M.S.S. was funded by Marató TVE, Consolider RNAREG (CSD2009-00080), and SAF2014-56868-R (Spanish Ministry of Economy and Innovation). J.V. was funded by Fundación Botín, Banco de Santander through its Santander Universities Global Division, Consolider RNAREG (CSD2009-00080), AGAUR and the European Research Council, and acknowledges support of the Spanish Ministry of Economy and Competitiveness, Centro de Excelencia Severo Ochoa 2013-2017. J.L.R.-P. was funded by grant FIS 2014/1737, and P.L.O.-R. by FIS 14/1784 from the Spanish Ministry of Health. E.E. was funded by grants BIO2011-23920, Consolider RNAREG (CSD2009-00080), by AGAUR (2014-SGR1121) and by the Sandra Ibarra Foundation for Cancer (FSI2013). The CNIO Proteomics Unit belongs to ProteoRed, PRB2- ISCIII, supported by grant PT13/0001. J.M. was supported by the Ramon y Cajal Programme (MINECO) RYC-2012-10651. H.G. and F.K. were funded by the China Scholarship Council, the Deutsche Forschungsgemeinschaft (DFG KA 2799/1) and the START Program of the Faculty of Medicine of the RWTH Aachen University. M.C. and P.K. were funded by predoctoral fellowships from Fundación La Caixa, and C.T. from SAF2014-56868-R. E.R.-F. was a recipient of a postdoctoral fellowship from “Fundación Científica de la Asociación Española Contra el Cáncer” and was also supported by FMM-2013/0075 of Fundacion Mutua Madrileña.