The complex role of NRF2 in cancer: A genomic view

Heterotrophs are regularly exposed to harmful xenobiotics from their diet and from environmental exposure. As such, systems to counteract the negative consequences brought on by this exposure have evolved since the dawn of heterotrophic nutrition. In mammalian cells, the CNC transcription factor, NRF2, plays a crucial role in counteracting the harmful effects of xenobiotics exposure. In response to increased electrophilic and oxidative stresses, NRF2 upregulates a wide array of target genes involved in various cellular processes to restore cellular homeostasis. Consequently, NRF2 activation is traditionally regarded as cancer preventative and cytoprotective. However, recent cancer genome sequencing efforts have uncovered a significant overrepresentation of somatic mutations that drive a sustained NRF2 activation phenotype in cancer. These mutations share similar features to somatic mutations in tumor suppressors and oncogenes, indicating that NRF2 activation is positively selected for during tumor growth. Additionally, genome wide determination of NRF2 target genes identified new target genes involved in proliferation and differentiation, metabolism, apoptosis, and DNA damage repair. NRF2 activation in cancer cells has also been correlated with chemo- and radio- therapy resistance and an overall poorer patient prognosis. Taken together, these characteristics of NRF2 function have established a need to better understand the full scope of the NRF2 regulatory network. In this review we discuss recent discoveries in the NRF2 field that were enabled by advances in genomic and computational biology methods and outline possible future endeavors.