An epigenetic switch controls an alternative NR2F2 isoform that unleashes a metastatic program in melanoma
Davalos, Veronica (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Lovell, Claudia D. (New York University School of Medicine, USA)
Von Itter, Richard (New York University School of Medicine, USA)
Dolgalev, Igor (New York University Grossman School of Medicine, USA)
Agrawal, Praveen (New York University Grossman School of Medicine, USA)
Baptiste, Gillian (New York University Grossman School of Medicine, USA)
Kahler, David J. (New York University Grossman School of Medicine, USA)
Sokolova, Elena (New York University Grossman School of Medicine, USA)
Moran, S (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Piqué, Laia (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Vega-Saenz de Miera, Eleazar (New York University School of Medicine, USA)
Fontanals-Cirera, Barbara (New York University School of Medicine, USA)
Karz, Alcida (New York University School of Medicine, USA)
Tsirigos, Aristotelis (New York University Grossman School of Medicine, USA)
Yun, Chi (New York University Grossman School of Medicine, USA)
Darvishian, Farbod (New York University Grossman School of Medicine, USA)
Etchevers, Heather C. (Aix-Marseille University, Marseille, France)
Osman, Iman (New York University Grossman School of Medicine, USA)
Esteller, M (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Schober, Markus (New York University School of Medicine, USA)
Hernando, Eva (New York University Grossman School of Medicine, USA)

Data:	2023
Resum:	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-to-mesenchymal 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-binding domain. 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 melanoma progression 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.
Ajuts:	European Commission 623443
Nota:	Altres ajuts: Laura and Isaac Perlmutter Cancer Center Support Grant (CCSG) NIH/NCI P30CA016087 (NIH/NCI); National Institute of Health S10 Grants NIH/ORIP S10OD01058 and S10OD018338; NCI/NIH R01CA202027, R01CA274100, P01CA206980, U54CA263001 (NYULH MetNet Center) and NYU Melanoma SPORE P50CA225450 (PI: I.O)
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Nature communications, Vol. 14 Núm. 1 (april 2023) , ISSN 2041-1723

DOI: 10.1038/s41467-023-36967-2
PMID: 37015919

16 p, 3.7 MB

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Documents de recerca > Documents dels grups de recerca de la UAB > Centres i grups de recerca (producció científica) > Ciències de la salut i biociències > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Institut de Recerca contra la Leucèmia Josep Carreras
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