Vera Olga, Martinez Michael, Soto-Vargas Zulaida, Wang Kaizhen, Xu Xiaonan, Ruiz-Buceta Sara, Mecozzi Nicol, Chadourne Manon, Posorske Benjamin, Angarita Ariana, Bok Ilah, Liu Qian, Murikipudi Harini, Kim Yumi, Messina Jane L, Tsai Kenneth Y, Major Michael B, Lau Eric K, Yu Xiaoqing, Ibanez-de-Caceres Inmaculada, Karreth Florian A
Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA.
Biomarkers and Experimental Therapeutics in Cancer, IdiPAZ, 28046 Madrid, Spain.
bioRxiv. 2024 Sep 6:2024.09.03.611024. doi: 10.1101/2024.09.03.611024.
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.
转录因子失调通过动态且可逆地控制基因表达程序，有力地推动黑色素瘤进展。我们之前鉴定出小MAF家族转录因子MAFG是黑色素瘤进展的一个假定驱动因素，这促使我们对其在黑色素瘤中的作用进行深入评估。MAFG的表达随人类黑色素瘤分期增加而升高，异位表达MAFG可增强人类黑色素瘤细胞在体外、异种移植模型以及自发性黑色素瘤基因小鼠模型中的恶性行为。此外，MAFG诱导黑色素瘤表型从黑素细胞状态转变为更去分化的状态。从机制上讲，MAFG与谱系转录因子MITF相互作用，而MITF是MAFG促肿瘤发生作用所必需的。MAFG和MITF共同占据众多基因组位点，MAFG过表达影响含有MAFG-MITF复合物结合位点的基因的表达。这些结果通过与MITF二聚化确立了MAFG作为黑色素瘤发生的有力驱动因素，并揭示了一种未被认识的MITF调节机制。
