Cancer Cell 20, 511–523 (2011)

Cancer Cell 20, 524–537 (2011)

The Krebs cycle enzyme fumarate hydratase (FH) is mutated in a hereditary renal cancer syndrome, where FH mutation stabilizes expression of HIF-1α, a transcription factor that promotes cell survival in hypoxic conditions. Because other HIF-1α–stabilizing mutations lead to distinct tumor phenotypes, two groups set out to determine whether FH mutation could promote tumorigenesis independently of HIF1α. Using genetic approaches, Ooi et al. and Adam et al. now link disruption of FH with loss of activity of KEAP1, an electrophile-sensitive component of an E3 ubiquitin ligase, and increased activity of the antioxidant response transcription factor NRF2. Both groups demonstrated that the link between FH mutation and KEAP1 or NRF2 is independent of HIF-1α. Fumarate, the substrate for FH, accumulates in FH-deficient cells; to mimic this state, Ooi et al. treated cells with dimethyl fumarate and found increased expression of NRF2 and its target genes, suggesting that KEAP1, which is known to control the stability of NRF2, is sensitive to fumarate. MS in both studies confirmed the modification of several residues in KEAP1 to S-(2-succinyl)-cysteine (2SC) in fumarate-accumulating conditions. Ooi et al. further demonstrated that ubiquitinated KEAP1 was elevated in FH-deficient cells compared to controls; additional experiments using proteasomal inhibitors led to a model where 2SC-modified KEAP1 is ubiquitinated and degraded by the proteasome. This is the first HIF-1α–independent mechanism proposed to explain tumorigenesis resulting from FH mutation; however, it remains to be determined how activation of the NRF2 antioxidant-response pathway contributes to oncogenesis in hereditary renal cancer.