Author:
Roider Elisabeth,Lakatos Alexandra I.T.,McConnell Alicia M.,Wang Poguang,Mueller Alina,Kawakami Akinori,Tsoi Jennifer,Szabolcs Botond L.,Ascsillán Anna A.,Suita Yusuke,Igras Vivien,Lo Jennifer A.,Hsiao Jennifer J.,Lapides Rebecca,Pál Dorottya M.P.,Lengyel Anna S.,Navarini Alexander,Okazaki Arimichi,Iliopoulos Othon,Németh István,Graeber Thomas G.,Zon Leonard,Giese Roger W.,Kemeny Lajos V.,Fisher David E.
Abstract
AbstractMicrophthalmia-associated transcription factor (MITF) plays pivotal roles in melanocyte development, function, and melanoma pathogenesis. MITF amplification occurs in melanoma and has been associated with resistance to targeted 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 damagein vivo. Some of the MITF target genes involved, such asIDH1andNNT, 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.One Sentence SummaryMITF promote melanoma survival via increasing ROS tolerance.
Publisher
Cold Spring Harbor Laboratory