Contributors: Department of Pathology, New York University Grossman School of Medicine, NY 10016, USA; Applied Bioinformatics Laboratories, New York University Grossman School of Medicine, NY 10016, USA; Bellvitge Biomedical Research Institute; Partenaires INRAE; Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Catalonia, Spain; New York University School of Medicine (NYU Grossman School of Medicine); National Tsing Hua University Hsinchu (NTHU); City University of Hong Kong Hong Kong (CUHK); Marseille medical genetics - Centre de génétique médicale de Marseille (MMG); Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM); Institut Marseille Maladies Rares (MarMaRa); Aix Marseille Université (AMU); Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York University School of Medicine, NY 10016, USA (NYUSM); Institució Catalana de Recerca i Estudis Avançats = Catalan Institution for Research and Advanced Studies (ICREA); Josep Carreras Leukaemia Research Institute (IJC); Centro de Investigación Biomédica en Red de Cáncer (CIBERONC); Universitat de Barcelona (UB); New York University New York (NYU); NYU System (NYU); We thank the NYU Experimental Pathology Core, the NYU Genome Technology Center, the NYUCenter for Biospecimen Research and Development, and the Small Animal Imaging core, all partially supported by the Laura and Isaac Perlmutter Cancer Center Support Grant (CCSG) NIH/NCI P30CA016087 (NIH/NCI), and National Institute of Health S10 Grants NIH/ORIP S10OD01058 and S10OD018338. We thank the High Throughput Biology Core partially funded by P30CA16087 and NYSTEM Contract C026719. V.D. was supported by the People Program (Marie Curie Actions) of the European Union's Seventh Framework Program (FP7-PEOPLE30 2013-IOF) under REA grant agreement n° PIOF-GA-2013-623443. This work was funded by NCI/NIH R01CA202027, R01CA274100, P01CA206980 and NYU Melanoma SPOREP50CA225450 (PI: I.O).
نبذة مختصرة : International audience ; Metastatic melanoma develops once transformed melanocytic cells begin to de-differentiate into migratory and invasive melanoma cells with neural crest cell (NCC)-like and epithelial-tomesenchymal transition (EMT)-like features. However, it is still unclear how transformed melanocytes assume a metastatic melanoma cell state. Here, we define DNA methylation changes that accompany metastatic progression in melanoma patients and discover Nuclear Receptor Subfamily 2 Group F, Member 2 – isoform 2 (NR2F2-Iso2) as an epigenetically regulated metastasis driver. NR2F2-Iso2 is transcribed from an alternative transcriptional start site (TSS) and it is truncated at the N-terminal end which encodes the NR2F2 DNA-bindingdomain. We find that NR2F2-Iso2 expression is turned off by DNA methylation when NCCs differentiate into melanocytes. Conversely, this process is reversed during metastatic melanoma progression, when NR2F2-Iso2 becomes increasingly hypomethylated and re-expressed. Our functional and molecular studies suggest that NR2F2-Iso2 drives metastatic melanomaprogression by modulating the activity of full-length NR2F2 (Isoform 1) over EMT- and NCC-associated target genes. Our findings indicate that DNA methylation changes play a crucial role during metastatic melanoma progression, and their control of NR2F2 activity allows transformed melanocytes to acquire NCC-like and EMT-like features. This epigenetically regulated transcriptional plasticity facilitates cell state transitions and metastatic spread.
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