NRF2 and Key Transcriptional Targets in Melanoma Redox Manipulation

Simple Summary Melanocytes are the pigment-producing cells in the skin that help to protect it against damaging solar ultraviolet radiation. As they engage in this function, they are subject to an inordinate amount of oxidative stress. To protect themselves, they utilize numerous antioxidant systems to reduce the amount of reactive oxygen and nitrogen species present in the cells, and this activity then contributes towards the prevention of cancer formation. However, after the formation of melanomas these same antioxidant systems are often co-opted by the cancer in order to promote its uncontrolled growth and metastasis. The purpose of this review is to highlight how the melanocyte's antioxidant systems, regulated by the transcription factor NRF2 and its targets, are co-opted in melanomas and, therefore, could be targeted for novel therapies to treat melanomas going forward. 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