Cancer-associated mutations have been identified in the metabolic genes
succinate dehydrogenase (SDH),
fumarate hydratase (FH) and
isocitrate dehydrogenase (IDH), advancing and challenging our understanding of cellular function and disease mechanisms and providing direct links between dysregulated metabolism and
cancer. Some striking parallels exist in the cellular consequences of the genetic mutations within this triad of
cancer syndromes, including accumulation of oncometabolites and competitive inhibition of 2-oxoglutarate-dependent
dioxygenases, particularly,
hypoxia-inducible factor (HIF)
prolyl hydroxylases,
JmjC domain-containing histone demethylases (part of the JMJD family) and the ten-eleven translocation (TET) family of 5methyl
cytosine (5mC)
DNA hydroxylases. These lead to activation of HIF-dependent oncogenic pathways and inhibition of
histone and DNA demethylation. Mutations in FH, resulting in loss of
enzyme activity, predispose affected individuals to a rare
cancer,
hereditary leiomyomatosis and renal cell cancer (HLRCC), characterised by benign smooth muscle cutaneous and uterine tumours (leiomyomata) and an aggressive form of collecting duct and type 2 papillary
renal cancer. Interestingly, loss of FH activity results in the accumulation of high levels of
fumarate that can lead to the non-enzymatic modification of
cysteine residues in multiple
proteins (succination) and in some cases to their disrupted function. Here we consider that the study of
rare diseases such as HLRCC, combining analyses of human tumours and cell lines with in vitro and in vivo murine models has provided novel insights into
cancer biology associated with dysregulated metabolism and represents a useful paradigm for
cancer research.