The Temporal and Contextual Relationship of NRF2 Activation and Cancer

Abstract

The complex role of NRF2 in the context of cancer continues to evolve. As a transcription factor, NRF2 regulates various genes involved in redox homeostasis, protein degradation, DNA repair, and xenobiotic metabolism. As such, NRF2 is critical in preserving cell function and viability, particularly during stress. Importantly, NRF2 itself is regulated via a variety of mechanisms, and the mode of NRF2 activation often dictates the duration of NRF2 signaling and its role in either preventing cancer initiation or promoting cancer progression. Herein, we highlight the light (chemoprevention) and dark (cancer progression) sides of NRF2 in cancer via three separate studies that explore the role of NRF2 in protecting against radiation-induced dermatitis, as well as the involvement of NRF2 in metastatic potential of melanoma and NSCLC. In the context of the light side of NRF2, pharmacological induction of NRF2 using bixin increased cellular glutathione levels which in turn combatted oxidative stress and mitigated radiation-induced dermatitis in non-cancerous skin keratinocytes. Meanwhile, in relation to the dark side of NRF2, in BRAF V600E mutant melanoma, cellular localization changes of FAM129B facilitates its binding with KEAP1, which in turn induced NRF2 and increased metastatic potential. Further work in arsenic-transformed bronchial cells and NSCLC revealed that NRF2 increases metastatic potential via upregulation of pro-metastatic transcription factor SOX9. Taken together, these data indicate that activation of NRF2 could be beneficial or detrimental to patient outcomes depending on the normal or cancerous state of the cell. Overall, a better understanding of the intricate nature of NRF2 regulation in specific cancer contexts should facilitate the generation of novel therapeutics designed to not only prevent tumor initiation, but also halt progression and ultimately improve patient wellbeing and survival.