TY - JOUR
T1 - The complex role of NRF2 in cancer
T2 - A genomic view
AU - Praslicka, Brandon John
AU - Kerins, Michael John
AU - Ooi, Aikseng
N1 - Publisher Copyright:
© 2016
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - CUL3
KW - Cancer
KW - KEAP1
KW - NRF2
KW - Somatic mutations
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U2 - 10.1016/j.cotox.2016.09.003
DO - 10.1016/j.cotox.2016.09.003
M3 - Review article
AN - SCOPUS:85016782538
SN - 2468-2020
VL - 1
SP - 37
EP - 45
JO - Current Opinion in Toxicology
JF - Current Opinion in Toxicology
ER -