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<p>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.</p>

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A MAFG~MITF complex drives melanoma phenotype switching and progression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月21日

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  • Olga Vera,
  • Michael Martinez,
  • Zulaida Soto-Vargas,
  • Kaizhen Wang,
  • Xiaonan Xu,
  • Nicol Mecozzi,
  • Harini Murikipudi,
  • Sara Ruiz-Buceta,
  • Manon Chadourne,
  • Benjamin Posorske,
  • Ariana Angarita,
  • Ilah Bok,
  • Juan D. Ulloa Arrieta,
  • Qian Liu,
  • Yumi Kim,
  • Jane L. Messina,
  • Kenneth Y. Tsai,
  • Michael B. Major,
  • Eric K. Lau,
  • Xiaoqing Yu,
  • Inmaculada Ibanez de Caceres,
  • Florian A. Karreth

摘要

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.