MITF regulates IDH1, NNT, and a transcriptional program protecting melanoma from reactive oxygen species

Roider, Elisabeth and I. T. Lakatos, Alexandra and McConnell, Alicia M. and Wang, Poguang and Mueller, Alina and Kawakami, Akinori and Tsoi, Jennifer and L. Szabolcs, Botond and A. Ascsillán, Anna and Suita, Yusuke and Igras, Vivien and A. Lo, Jennifer and J. Hsiao, Jennifer and Lapides, Rebecca and Pál, Dorottya M. P. and Lengyel, Anna S. and Navarini, Alexander and Okazaki, Arichimi and Iliopoulos, Othon and Németh, István and Graeber, Thomas G. and Zon, Leonard and Giese, Roger W. and Kemény, Lajos Vince and Fischer, David E. (2024) MITF regulates IDH1, NNT, and a transcriptional program protecting melanoma from reactive oxygen species. SCIENTIFIC REPORTS, 14. No.-21527. ISSN 2045-2322

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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.

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