Nuclear 3’-end-polyadenylation is essential for the transport, stability and translation of virtually all eukaryotic mRNAs. Poly(A) tail extension can also occur in the cytoplasm, but the transcripts involved are incompletely understood, particularly in cancer. Here we identify a lineage-specific requirement of the cytoplasmic polyadenylation binding protein 4 (CPEB4) in malignant melanoma. CPEB4 is upregulated early in melanoma progression, as defined by computational and histological analyses. Melanoma cells are distinct from other tumour cell types in their dependency on CPEB4, not only to prevent mitotic aberrations, but to progress through G1/S cell cycle checkpoints. RNA immunoprecipitation, sequencing of bound transcripts and poly(A) length tests link the melanoma-specific functions of CPEB4 to signalling hubs specifically enriched in this disease. Essential in these CPEB4-controlled networks are the melanoma drivers MITF and RAB7A, a feature validated in clinical biopsies. These results provide new mechanistic links between cytoplasmic polyadenylation and lineage specification in melanoma.

M.S.S. was funded by Marató TVE and Consolider RNAREG (CSD2009-00080), and SAF2014-56868-R (Spanish Ministry of Economy and Innovation). R.M. was supported by Fundación Botín, by the Banco Santander through its Santander Universities Global Division, and by grants from the Spanish Ministry of Economy and Innovation (BFU2011–30121 and Consolider RNAREG (CSD2009-00080). J.L.R.-P. was funded by grant FIS 2014/1737 from the Spanish Ministry of Health, P.L.O.-R. by FIS 14/1784; and N.B. and E.E. by MINECO and FEDER (BIO2014-52566-R), as well as by Consolider RNAREG (CSD2009-00080), by AGAUR (2014-SGR1121) and by the Sandra Ibarra Foundation for Cancer (FSI2013). C.R.G was funded by Ludwig Institute for Cancer Research. E.P.-G., D.A.-C. and R.M.-H. are recipients of Scientists in Training predoctoral fellowships from the Spanish Ministry of Science and Innovation. P.K and M.C. are funded by a predoctoral fellowship from Fundación La Caixa. E.R.-F. is the recipient of a postdoctoral fellowship from ‘Fundación Científica de la Asociación Española Contra el Cáncer’ and supported by FMM-2013/0075 of Fundacion Mutua Madrileña.