Citation

Roider E, Lakatos AIT, McConnell AM, Wang P, Mueller A, Kawakami A, Tsoi J, Szabolcs BL, Ascsillán AA, Suita Y, Igras V, Lo JA, Hsiao JJ, Lapides R, Pál DMP, Lengyel AS, Navarini A, Okazaki A, Iliopoulos O, Németh I, Graeber TG, Zon L, Giese RW, Kemeny LV, Fisher DE. 2024. MITF regulates IDH1, NNT, and a transcriptional program protecting melanoma from reactive oxygen species. Scientific reports. 14(1):21527. Pubmed: 39277608 DOI:10.1038/s41598-024-72031-9

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.
© 2024. The Author(s).

Related Faculty

Photo of Len Zon

The Zon laboratory aims to dissect how assaults to the hematopoietic system cause severe diseases such as leukemias, lymphomas, and anemias. They investigate hematopoietic development and disease using chemical screens, genetic screens, and analysis of novel transgenic lines in zebrafish.

Search Menu