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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 KEAP1โNRF2 interaction, (4) transcriptional up-regulation of NRF2 gene through oncogene-dependent signaling, and (5) the modification of KEAP1 protein through oncometabolites
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