An epigenetic switch controls an alternative NR2F2 isoform that unleashes a metastatic program in melanoma
Verónica Dávalos, Claudia D. Lovell, Richard Von Itter, Igor Dolgalev, Praveen Agrawal, Gillian Baptiste, David J. Kahler, Elena Sokolova, Sebastián Morán, Laia Piqué, Eleazar Vega‐Saenz de Miera, Bárbara Fontanals-Cirera, Alcida Karz, Aristotelis Tsirigos, Chi Young Yun, Farbod Darvishian, Heather Etchevers, Iman Osman, Manel Esteller, Markus Schöber, Eva Hernando
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.