An epigenetic switch controls an alternative NR2F2 isoform that unleashes a metastatic program in melanoma.

Autor: Davalos V; Department of Pathology, New York University Grossman School of Medicine, New York, NY, 10016, USA. vdavalos@carrerasresearch.org.; Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA. vdavalos@carrerasresearch.org.; Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Catalonia, Spain. vdavalos@carrerasresearch.org., Lovell CD; Department of Pathology, New York University Grossman School of Medicine, New York, NY, 10016, USA.; Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA., Von Itter R; Department of Pathology, New York University Grossman School of Medicine, New York, NY, 10016, USA.; Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA., Dolgalev I; Applied Bioinformatics Laboratories, New York University Grossman School of Medicine, New York, NY, 10016, USA., Agrawal P; Department of Pathology, New York University Grossman School of Medicine, New York, NY, 10016, USA.; Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA.; Department of Molecular Pharmacology, Albert Einstein College of Medicine/ Montefiore, Bronx, NY, 10461, USA., Baptiste G; Department of Pathology, New York University Grossman School of Medicine, New York, NY, 10016, USA.; Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA., Kahler DJ; High Throughput Biology Core, New York University Grossman School of Medicine, New York, NY, 10016, USA., Sokolova E; Department of Pathology, New York University Grossman School of Medicine, New York, NY, 10016, USA.; Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA., Moran S; Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Catalonia, Spain., Piqué L; Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Catalonia, Spain., Vega-Saenz de Miera E; Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA.; The Ronald O. Perelman Department of Dermatology, New York University Grossman School of Medicine, New York, NY, 10016, USA., Fontanals-Cirera B; Department of Pathology, New York University Grossman School of Medicine, New York, NY, 10016, USA.; Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA., Karz A; Department of Pathology, New York University Grossman School of Medicine, New York, NY, 10016, USA.; Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA., Tsirigos A; Department of Pathology, New York University Grossman School of Medicine, New York, NY, 10016, USA.; Applied Bioinformatics Laboratories, New York University Grossman School of Medicine, New York, NY, 10016, USA., Yun C; High Throughput Biology Core, New York University Grossman School of Medicine, New York, NY, 10016, USA., Darvishian F; Department of Pathology, New York University Grossman School of Medicine, New York, NY, 10016, USA.; Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA., Etchevers HC; Aix-Marseille University, MMG, Inserm, U1251, Marseille, France., Osman I; Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA.; The Ronald O. Perelman Department of Dermatology, New York University Grossman School of Medicine, New York, NY, 10016, USA., Esteller M; Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Catalonia, Spain.; Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Catalonia, Spain.; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.; Centro de Investigacion Biomedica en Red, Cancer (CIBERONC), Madrid, Spain., Schober M; Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA. Markus.Schober@nyulangone.org.; The Ronald O. Perelman Department of Dermatology, New York University Grossman School of Medicine, New York, NY, 10016, USA. Markus.Schober@nyulangone.org.; Department of Cell Biology, New York Grossman University School of Medicine, New York, NY, 10016, USA. Markus.Schober@nyulangone.org., Hernando E; Department of Pathology, New York University Grossman School of Medicine, New York, NY, 10016, USA. Eva.Hernando-Monge@nyulangone.org.; Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA. Eva.Hernando-Monge@nyulangone.org.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Apr 04; Vol. 14 (1), pp. 1867. Date of Electronic Publication: 2023 Apr 04.
DOI: 10.1038/s41467-023-36967-2
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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