RNA binding proteins (RBPs) modulate cancer progression through poorly understood mechanisms. Here we show that the RBP UNR/CSDE1 is overexpressed in melanoma tumors and promotes invasion and metastasis. iCLIP sequencing, RNA sequencing, and ribosome profiling combined with in silico studies unveiled sets of pro-metastatic factors coordinately regulated by UNR as part of RNA regulons. In addition to RNA steady-state levels, UNR was found to control many of its targets at the level of translation elongation/termination. Key pro-oncogenic targets of UNR included VIM and RAC1, as validated by loss- and gain-of-function studies. Our results identify UNR as an oncogenic modulator of melanoma progression, unravel the underlying molecular mechanisms, and identify potential targets for this therapeutically challenging malignancy.

L.W. was supported by the Fonds National de la Recherche, Luxembourg, and cofunded by the Marie Curie Actions of the European Commission (FP7-COFUND) (Project Code 1072489). M.G.-F. was supported by a Juan de la Cierva fellowship from the Spanish Ministry of Economy and Competitiveness (MINECO). This work was supported by MINECO and the European Regional Development Fund (ERDF) under grant BFU2012-37135 and BFU2015-68741 to F.G., and Consolider CSD2009-00080 and TV’13-20131430 (Marató de TV3) grants to F.G. and M.S.S. We acknowledge support of the Spanish Ministry of Economy and Competitiveness, Centro de Excelencia Severo Ochoa 2013–2017, SEV-2012-0208 (to CRG) and SEV-2011-0191 (to CNIO)