Establishing the Hungarian Center of Excellence for Molecular Medicine in partnership
with EMBL(739593) Funder: Horizon 2020
Subjects:
Clinical medicine
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.
