1. MITF regulates IDH1, NNT, and a transcriptional program protecting melanoma from reactive oxygen species
- Author
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Elisabeth Roider, Alexandra I. T. Lakatos, Alicia M. McConnell, Poguang Wang, Alina Mueller, Akinori Kawakami, Jennifer Tsoi, Botond L. Szabolcs, Anna A. Ascsillán, Yusuke Suita, Vivien Igras, Jennifer A. Lo, Jennifer J. Hsiao, Rebecca Lapides, Dorottya M. P. Pál, Anna S. Lengyel, Alexander Navarini, Arimichi Okazaki, Othon Iliopoulos, István Németh, Thomas G. Graeber, Leonard Zon, Roger W. Giese, Lajos V. Kemeny, and David E. Fisher
- Subjects
Medicine ,Science - Abstract
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.
- Published
- 2024
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