KEAP1 and cancer: Several mechanisms have been reported for the increased activity of NRF2 in cancers (Figure 5): (1) somatic mutations in KEAP1 or NRF2, (2) DNA hypermethylation at the promoter region of KEAP1, (3) the aberrant accumulation of proteins that disrupt the KEAP1–NRF2 interaction, (4) transcriptional up-regulation of NRF2 gene through oncogene-dependent signaling, and (5) the modification of KEAP1 protein through oncometabolites.