MITF regulates IDH1, NNT, and a transcriptional program protecting melanoma from reactive oxygen species
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.
Authors
- Anna Lengyel (ORCID: https://orcid.org/0000-0002-3477-7411)
- Poguang Wang (ORCID: https://orcid.org/0000-0002-2962-0495)
- Alicia M. McConnell (ORCID: https://orcid.org/0000-0002-0984-4045)
- Vivien Igras
- Yusuke Suita (ORCID: https://orcid.org/0000-0002-8387-4162)
- Thomas G. Graeber (ORCID: https://orcid.org/0000-0001-8574-9181)
- Arimichi Okazaki
- Othon Iliopoulos (ORCID: https://orcid.org/0000-0002-4444-6157)
- Roger W. Giese
- Alexander A. Navarini (ORCID: https://orcid.org/0000-0001-7059-632X)
- Rebecca Lapides
- D. Pal (ORCID: https://orcid.org/0000-0002-9426-487X)
- Alina Mueller (ORCID: https://orcid.org/0000-0002-3927-336X)
- Anna A. Ascsillán (ORCID: https://orcid.org/0000-0002-9415-6887)
- Elisabeth Roider (ORCID: https://orcid.org/0000-0003-0817-1923)
- Akinori Kawakami (ORCID: https://orcid.org/0000-0001-7239-7236)
- David E. Fisher (ORCID: https://orcid.org/0000-0002-5506-0575)
- Leonard Ira Zon (ORCID: https://orcid.org/0000-0003-0860-926X)
- Botond L. Szabolcs
- Jennifer Tsoi (ORCID: https://orcid.org/0000-0001-7269-5161)
- Jennifer J. Hsiao
- Lajos V Kemeny
- I Németh
- Jennifer A. Lo (ORCID: https://orcid.org/0000-0002-9520-6874)
- Alexandra I.T. Lakatos
Institutions
- Semmelweis University (HU)
- University of Vermont (US)
- Northeastern University (US)
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- University of California, Los Angeles (US)
- University of Szeged (HU)
- University Hospital of Basel (CH)
- Massachusetts General Hospital (US)
- Dana-Farber Cancer Institute (US)
- Dana-Farber/Harvard Cancer Center (US)
- Center for Cancer Research (US)
- Eastern University (BD)
- Institute for Molecular Medicine (US)
Publication Details
- Journal
- Scientific Reports
- Published
- 2024-09-14
- DOI
- https://doi.org/10.1038/s41598-024-72031-9
- Citations
- 10
- Primary Topic
- melanin and skin pigmentation
- Type
- article
- Field-Weighted Citation Impact
- 3.26
Funders
- Melanoma Research Alliance
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Harvard University
- Harvard Catalyst
- Semmelweis Egyetem
- Hungarian Scientific Research Fund
- Magyar Tudományos Akadémia
- Universität Zürich
- National Institutes of Health
- National Research, Development and Innovation Office
- National Center for Advancing Translational Sciences