Figure 7.

The Potential Roles of Fumarate as an Oncometabolite

The KEAP1 protein is part of an E3 ubiquitin ligase, which under normal physiological conditions targets NRF2 for polyubiquitination and subsequent degradation (Zhang, 2006). Critical cysteine residues in KEAP1 are modified by fumarate via succination. We propose that succination impairs the ability of KEAP1 to negatively regulate NRF2, thus facilitating transcription of genes that contain an ARE (Nguyen et al., 2003) in the promoter region.