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

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

doi:10.1038/s41598-024-72031-9

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

Sci Rep. 2024 Sep 14;14(1):21527. doi: 10.1038/s41598-024-72031-9.

Authors

Elisabeth Roider^#^{1

2

3}, Alexandra I T Lakatos^#^{4

5

6}, Alicia M McConnell⁷, Poguang Wang⁸, Alina Mueller⁹, Akinori Kawakami¹⁰, Jennifer Tsoi^{11

12}, Botond L Szabolcs^{4

5

6}, Anna A Ascsillán^{4

5

6}, Yusuke Suita¹⁰, Vivien Igras¹⁰, Jennifer A Lo¹⁰, Jennifer J Hsiao¹⁰, Rebecca Lapides^{10

13}, Dorottya M P Pál^{4

5

6}, Anna S Lengyel^{4

5

6}, Alexander Navarini⁹, Arimichi Okazaki¹⁴, Othon Iliopoulos¹⁴, István Németh¹⁵, Thomas G Graeber^{11

12

16}, Leonard Zon⁷, Roger W Giese⁸, Lajos V Kemeny^#^{17

18

19

20

21}, David E Fisher^#^{22

23

24}

Affiliations

¹ Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, USA. [email protected].
² Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA. [email protected].
³ Department of Dermatology, University Hospital of Basel, Basel, Switzerland. [email protected].
⁴ HCEMM-SU Translational Dermatology Research Group, Semmelweis University, Budapest, Hungary.
⁵ Department of Physiology, Semmelweis University, Budapest, Hungary.
⁶ Department of Dermatology, Venereology, and Dermatooncology, Semmelweis University, Budapest, Hungary.
⁷ Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Massachusetts and the Howard Hughes Medical Institute, Boston, USA.
⁸ Department of Pharmaceutical Sciences, Department of Chemistry and Chemical Biology, and Barnett Institute, Bouve College, Northeastern University, Boston, MA, 02115, USA.
⁹ Department of Dermatology, University Hospital of Basel, Basel, Switzerland.
¹⁰ Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
¹¹ Department of Molecular and Medical Pharmacology, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
¹² UCLA Metabolomics Center, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
¹³ Robert Larner, College of Medicine at the University of Vermont, Burlington, USA.
¹⁴ Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA.
¹⁵ Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary.
¹⁶ Crump Institute for Molecular Imaging, UCLA, Los Angeles, CA, USA.
¹⁷ Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, USA. [email protected].
¹⁸ Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA. [email protected].
¹⁹ HCEMM-SU Translational Dermatology Research Group, Semmelweis University, Budapest, Hungary. [email protected].
²⁰ Department of Physiology, Semmelweis University, Budapest, Hungary. [email protected].
²¹ Department of Dermatology, Venereology, and Dermatooncology, Semmelweis University, Budapest, Hungary. [email protected].
²² Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, USA. [email protected].
²³ Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA. [email protected].
²⁴ Lancer Professorship of Dermatology, Harvard Medical School, Boston, USA. [email protected].

^# Contributed equally.

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.

MeSH terms

Animals
Cell Line, Tumor
DNA Damage
Gene Expression Regulation, Neoplastic*
Humans
Isocitrate Dehydrogenase* / genetics
Isocitrate Dehydrogenase* / metabolism
Melanoma* / genetics
Melanoma* / metabolism
Melanoma* / pathology
Microphthalmia-Associated Transcription Factor* / genetics
Microphthalmia-Associated Transcription Factor* / metabolism
Reactive Oxygen Species* / metabolism
Transcription, Genetic
Zebrafish Proteins / genetics
Zebrafish Proteins / metabolism
Zebrafish*

Substances

Microphthalmia-Associated Transcription Factor
Reactive Oxygen Species
Isocitrate Dehydrogenase
MITF protein, human
IDH1 protein, human
Zebrafish Proteins

Abstract

MeSH terms

Substances

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