title: Lineage-specific roles of the cytoplasmic polyadenylation factor CPEB4 in the regulation of melanoma drivers.
abstract: 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.
authors.affiliation: Melanoma Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Pérez-Guijarro
authors.affiliation: Melanoma Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Karras
authors.affiliation: Melanoma Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors.forename: Metehan
authors.initials: M
authors.lastname: Cifdaloz
authors.affiliation: Melanoma Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors.forename: Raúl
authors.initials: R
authors.lastname: Martínez-Herranz
authors.affiliation: Melanoma Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors.forename: Estela
authors.initials: E
authors.lastname: Cañón
authors.affiliation: Bioinformatics Unit (CNIO), Madrid 28029, Spain.
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Graña
authors.affiliation: Department of Dermatology, Hospital Gregorio Marañón, Madrid 28003, Spain.
authors.forename: Celia
authors.initials: C
authors.lastname: Horcajada-Reales
authors.affiliation: Melanoma Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors.forename: Direna
authors.initials: D
authors.lastname: Alonso-Curbelo
authors.affiliation: Melanoma Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors.forename: Tonantzin G
authors.initials: TG
authors.lastname: Calvo
authors.affiliation: Bioinformatics Unit (CNIO), Madrid 28029, Spain.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Gómez-López
authors.affiliation: Department of Experimental and Health Sciences, Universidad Pompeu Fabra, Barcelona 08002, Spain.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bellora
authors.affiliation: Instituto de Investigación i+12, Hospital 12 de Octubre, Medical School, Universidad Complutense, Madrid 28041, Spain.
authors.forename: Erica
authors.initials: E
authors.lastname: Riveiro-Falkenbach
authors.affiliation: Instituto de Investigación i+12, Hospital 12 de Octubre, Medical School, Universidad Complutense, Madrid 28041, Spain.
authors.forename: Pablo L
authors.initials: PL
authors.lastname: Ortiz-Romero
authors.affiliation: Instituto de Investigación i+12, Hospital 12 de Octubre, Medical School, Universidad Complutense, Madrid 28041, Spain.
authors.forename: José L
authors.initials: JL
authors.lastname: Rodríguez-Peralto
authors.affiliation: Monoclonal Antibodies Unit, Biotechnology Programme (CNIO), Madrid 28029, Spain.
authors.forename: Lorena
authors.initials: L
authors.lastname: Maestre
authors.affiliation: Monoclonal Antibodies Unit, Biotechnology Programme (CNIO), Madrid 28029, Spain.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Roncador
authors.affiliation: Department of Pediatric Surgery, Hospital Gregorio Marañón, Madrid 28003, Spain.
authors.forename: Juan C
authors.initials: JC
authors.lastname: de Agustín Asensio
authors.affiliation: Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, Spain.
authors.forename: Colin R
authors.initials: CR
authors.lastname: Goding
authors.affiliation: Department of Experimental and Health Sciences, Universidad Pompeu Fabra, Barcelona 08002, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Eyras
authors.affiliation: Confocal Microscopy Unit, (CNIO) Madrid 28029, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Megías
authors.affiliation: Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain.|Translational Control of Cell Cycle and Differentiation Group, Molecular Medicine Department, Institute for Research in Biomedicine (IRB), The Barcelona Institute of Science and Technology, Barcelona 08028, Spain.
authors.forename: Raúl
authors.initials: R
authors.lastname: Méndez
authors.affiliation: Melanoma Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
authors.forename: María S
authors.initials: MS
authors.lastname: Soengas
mesh_terms: D000818:Animals; D002453:Cell Cycle; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009374:Neoplasms, Experimental; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C554939:CPEB4 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins