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- Title
MITF regulates IDH1, NNT, and a transcriptional program protecting melanoma from reactive oxygen species.
- Authors
Roider, Elisabeth; Lakatos, Alexandra I. T.; McConnell, Alicia M.; Wang, Poguang; Mueller, Alina; Kawakami, Akinori; Tsoi, Jennifer; Szabolcs, Botond L.; Ascsillán, Anna A.; Suita, Yusuke; Igras, Vivien; Lo, Jennifer A.; Hsiao, Jennifer J.; Lapides, Rebecca; Pál, Dorottya M. P.; Lengyel, Anna S.; Navarini, Alexander; Okazaki, Arimichi; Iliopoulos, Othon; Németh, István
- Abstract
Microphthalmia-associated transcription factor (MITF) is a master regulator of melanocyte function, development and plays a significant role in melanoma pathogenesis. MITF genomic amplification promotes melanoma development, and it can facilitate resistance to multiple therapies. Here, we show that MITF regulates a global antioxidant program that increases survival of melanoma cell lines by protecting the cells from reactive oxygen species (ROS)-induced damage. In addition, this redox program is correlated with MITF expression in human melanoma cell lines and patient-derived melanoma samples. Using a zebrafish melanoma model, we show that MITF decreases ROS-mediated DNA damage in vivo. Some of the MITF target genes involved, such as IDH1 and NNT, are regulated through direct MITF binding to canonical enhancer box (E-BOX) sequences proximal to their promoters. Utilizing functional experiments, we demonstrate the role of MITF and its target genes in reducing cytosolic and mitochondrial ROS. Collectively, our data identify MITF as a significant driver of the cellular antioxidant state.
- Publication
Scientific Reports, 2024, Vol 14, Issue 1, p1
- ISSN
2045-2322
- Publication type
Article
- DOI
10.1038/s41598-024-72031-9