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

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.

Oxidative Stress in Melanoma: Beneficial Antioxidant and Pro-Oxidant Therapeutic Strategies

“…However, aberrant overexpression of NRF2 increases antioxidant responses and changes the cellular redox state, aiding in melanoma cell survival, growth, and metastasis [70]. According to a recent study by Davalos et al, Nuclear Receptor Subfamily 2 Group F, Member 2-isoform 2 (NRF2F2-Iso2) promotes the progression of metastatic melanoma by influencing the activity of full-length NR2F2 on neural crest cell (NCC) and epithelial-tomesenchymal transition (EMT) target genes [71]. Importantly, NRF2 may promote invasion and migration by upregulating HO-1 [72].…”

Epigenetic regulation of mRNA mediates the phenotypic plasticity of cancer cells during metastasis and therapeutic resistance (Review)

“…This aberrant DNA methylation in cancer cells enhances cellular plasticity and promotes adaptability and resistance to treatments ( 43 ). Davalos et al ( 44 ) reported that DNA methylation changes accompany the metastasis of melanoma, and nuclear receptor subfamily 2 group F, member 2 isoform (NR2F2-Iso2) is a transfer-driven factor involved in epigenetic regulation. Neural crest cells (NCCs) differentiate into melanocytes upon the inhibition of NR2F2-Iso2 expression via DNA methylation, whereas NR2F2-Iso2 is increasingly hypomethylated and re-expressed in metastatic melanoma.…”

“…Neural crest cells (NCCs) differentiate into melanocytes upon the inhibition of NR2F2-Iso2 expression via DNA methylation, whereas NR2F2-Iso2 is increasingly hypomethylated and re-expressed in metastatic melanoma. Therefore, it was indicated that DNA methylation changes allow transformed melanocytes to acquire NCC- and EMT-like features by controlling NR2F2 activity ( 44 ). In addition, Mancini et al ( 45 ) revealed that the deregulation of DNMTs and several microRNAs (miRNAs) has a relevant role in EMT of prostate cancer cells.…”