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

Veronica Davalos (), Claudia D. Lovell, Richard Itter, Igor Dolgalev, Praveen Agrawal, Gillian Baptiste, David J. Kahler, Elena Sokolova, Sebastian Moran, Laia Piqué, Eleazar Vega-Saenz de Miera, Barbara Fontanals-Cirera, Alcida Karz, Aristotelis Tsirigos, Chi Yun, Farbod Darvishian, Heather C. Etchevers, Iman Osman, Manel Esteller, Markus Schober () and Eva Hernando ()
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Veronica Davalos: New York University Grossman School of Medicine
Claudia D. Lovell: New York University Grossman School of Medicine
Richard Itter: New York University Grossman School of Medicine
Igor Dolgalev: New York University Grossman School of Medicine
Praveen Agrawal: New York University Grossman School of Medicine
Gillian Baptiste: New York University Grossman School of Medicine
David J. Kahler: New York University Grossman School of Medicine
Elena Sokolova: New York University Grossman School of Medicine
Sebastian Moran: Josep Carreras Leukaemia Research Institute (IJC), Badalona
Laia Piqué: Josep Carreras Leukaemia Research Institute (IJC), Badalona
Eleazar Vega-Saenz de Miera: New York University School of Medicine
Barbara Fontanals-Cirera: New York University Grossman School of Medicine
Alcida Karz: New York University Grossman School of Medicine
Aristotelis Tsirigos: New York University Grossman School of Medicine
Chi Yun: New York University Grossman School of Medicine
Farbod Darvishian: New York University Grossman School of Medicine
Heather C. Etchevers: Aix-Marseille University, MMG, Inserm
Iman Osman: New York University School of Medicine
Manel Esteller: Josep Carreras Leukaemia Research Institute (IJC), Badalona
Markus Schober: New York University School of Medicine
Eva Hernando: New York University Grossman School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-36967-2

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