A MAFG~MITF complex drives melanoma phenotype switching and progression

Abstract

Abstract Phenotype switching, a key driver of melanoma progression and therapy resistance, is governed by the lineage transcription factor MITF. Here, we identify the small MAF family transcription factor MAFG as a critical regulator of MITF activity and melanoma cell state plasticity. MAFG expression is frequently elevated in melanoma and correlates with poor patient survival. Mechanistically, MAFG binds MITF and redirects its genomic occupancy, thereby modulating transcriptional programs governed by MITF. Genetic perturbation studies in vitro and in vivo show that MAFG promotes a dedifferentiated cell state and accelerates melanoma progression through its direct interaction with MITF. Moreover, MAFG is required for melanoma cell proliferation and for the transition from nevi to melanoma in genetic mouse models. Together, these findings demonstrate that the MAFG~MITF complex orchestrates phenotype switching and tumor progression, uncovering an unrecognized mechanism of MITF regulation in melanoma.