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

Authors :
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
David E. Fisher
Source :
Scientific Reports, Vol 14, Iss 1, Pp 1-13 (2024)
Publication Year :
2024
Publisher :
Nature Portfolio, 2024.

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.

Subjects

Subjects :
Medicine
Science

Details

Language :
English
ISSN :
20452322
Volume :
14
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Scientific Reports
Publication Type :
Academic Journal
Accession number :
edsdoj.94d2d3111647cfb25391c16c6a03e3
Document Type :
article
Full Text :
https://doi.org/10.1038/s41598-024-72031-9