NRF2 and Key Transcriptional Targets in Melanoma Redox Manipulation

Abstract

Melanocytes are dendritic, pigment-producing cells located in the skin and are responsible for its protection against the deleterious effects of solar ultraviolet radiation (UVR), which include DNA damage and elevated reactive oxygen species (ROS). They do so by synthesizing photoprotective melanin pigments and distributing them to adjacent skin cells (e.g., keratinocytes). However, melanocytes encounter a large burden of oxidative stress during this process, due to both exogenous and endogenous sources. Therefore, melanocytes employ numerous antioxidant defenses to protect themselves; these are largely regulated by the master stress response transcription factor, nuclear factor erythroid 2-related factor 2 (NRF2). Key effector transcriptional targets of NRF2 include the components of the glutathione and thioredoxin antioxidant systems. Despite these defenses, melanocyte DNA often is subject to mutations that result in the dysregulation of the proliferative mitogen-activated protein kinase (MAPK) pathway and the cell cycle. Following tumor initiation, endogenous antioxidant systems are co-opted, a consequence of elevated oxidative stress caused by metabolic reprogramming, to establish an altered redox homeostasis. This altered redox homeostasis contributes to tumor progression and metastasis, while also complicating the application of exogenous antioxidant treatments. Further understanding of melanocyte redox homeostasis, in the presence or absence of disease, would contribute to the development of novel therapies to aid in the prevention and treatment of melanomas and other skin diseases