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.
Acknowledgements
We thank G. DeNicola for plasmids and J. Cleveland, K. Smalley, G. DeNicola, and members of the Karreth lab for helpful discussions. O.V.P. and I.I.d.C. were supported by Instituto de Salud Carlos III and co-funded by the European Union under Grants PI21/00145, PI24/00291, CD22/00040 and CP24/00005. X.X. received support from a Miles for Moffitt Postdoc Award and a Melanoma Research Foundation Career Development Award (1068914). I.B. was supported by a T32 training grant (CA113275). M.B.M. was supported by NIH grant R01CA244236. F.A.K. received funding from the American Cancer Society (RSG-21-087-01), Melanoma Research Alliance (https://doi.org/10.48050/pc.gr.75702), and NIH grants R01CA259046 and R21CA256141. This work was also supported by the Gene Targeting Core, Bioinformatics and Biostatistics Shared Resource, Molecular Genomics Core, Analytical Microscopy Core, which are funded in part by Moffitt’s Cancer Center Support Grant (P30CA076292).
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Vera, O., Martinez, M., Soto-Vargas, Z. et al. A MAFG~MITF complex drives melanoma phenotype switching and progression. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73291-x
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DOI: https://doi.org/10.1038/s41467-026-73291-x
