
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.09.03.611024
preprint
1
Article
The small MAF transcription factor MAFG co-opts MITF to promote melanoma progression
Vera Olga http://orcid.org/0000-0002-1878-4945

Martinez Michael
Soto-Vargas Zulaida http://orcid.org/0000-0002-3174-4104

Wang Kaizhen http://orcid.org/0000-0001-6033-7041

Xu Xiaonan http://orcid.org/0000-0002-7366-580X

Ruiz-Buceta Sara
Mecozzi Nicol http://orcid.org/0000-0001-6161-5074

Chadourne Manon
Posorske Benjamin http://orcid.org/0009-0003-7022-5547

Angarita Ariana
Bok Ilah http://orcid.org/0000-0001-8958-5161

Liu Qian
Murikipudi Harini
Kim Yumi http://orcid.org/0000-0001-8815-3121

Messina Jane L. http://orcid.org/0000-0002-0332-0224

Tsai Kenneth Y. http://orcid.org/0000-0001-5325-212X

Major Michael B. http://orcid.org/0000-0002-6753-8513

Lau Eric K. http://orcid.org/0000-0003-3005-3421

Yu Xiaoqing http://orcid.org/0000-0003-4585-9372

Ibanez-de-Caceres Inmaculada http://orcid.org/0000-0001-9805-8486

Karreth Florian A. http://orcid.org/0000-0002-2350-9809

06 9 2024
2024.09.03.611024https://creativecommons.org/licenses/by-nc/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.09.03.611024
nihpp-2024.09.03.611024.pdf
ABSTRACT

Transcription factor deregulation potently drives melanoma progression by dynamically and reversibly controlling gene expression programs. We previously identified the small MAF family transcription factor MAFG as a putative driver of melanoma progression, prompting an in-depth evaluation of its role in melanoma. MAFG expression increases with human melanoma stages and ectopic MAFG expression enhances the malignant behavior of human melanoma cells in vitro, xenograft models, and genetic mouse models of spontaneous melanoma. Moreover, MAFG induces a melanoma phenotype switch from a melanocytic state to a more dedifferentiated state. Mechanistically, MAFG interacts with the lineage transcription factor MITF which is required for the pro-tumorigenic effects of MAFG. MAFG and MITF co-occupy numerous genomic sites and MAFG overexpression influences the expression of genes harboring binding sites for the MAFG∼MITF complex. These results establish MAFG as a potent driver of melanomagenesis through dimerization with MITF and uncover an unappreciated mechanism of MITF regulation.

Significance statement

MITF is critically involved in melanoma progression and phenotype switching. We discovered that MAFG interacts with MITF to influence expression of MITF target genes and facilitate a shift toward a dedifferentiated melanoma cell state. This study demonstrates that MAFG promotes melanomagenesis by influencing MITF activity, an unappreciated mechanism of MITF regulation.
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