Novel Insights into FH-associated Disease are KEAPing the Lid on Oncogenic HIF Signalling

Abstract

Fumarate hydratase (FH) encodes a Krebs cycle enzyme which is mutated in hereditary leiomyomatosis and renal cell cancer (HLRCC). Fumarate is a potent inhibitor of a class of enzymes, 2-oxoglutarate (2OG) oxygenases, that require oxygen, non-haem Fe(II), and 2OG for activity. Importantly, loss of FH function has been shown to result in elevated levels of fumarate in cells and tumors. Recent work has demonstrated that fumarate-mediated inhibition of a sub-class of 2OG oxygenases, the hypoxia-inducible factor prolyl hydroxylase enzymes (HIF-PHDs), causes stabilisation of HIF and the upregulation of a broad range of HIF-target genes, including those that stimulate cell growth and angiogenesis, which may in turn contribute to tumorigenesis [1]. Previously we generated a conditional Fh1 (the ortholog of human FH) knockout mouse and showed that kidney-specific deletion of Fh1 recapitulated important aspects of the human disease, including activation of HIF and the development of hyperplastic renal cysts [2]. HIF dysregulation following inactivation of the FH tumor suppressor gene has therefore been hypothesised as a plausible mechanism for HLRCC tumorigenesis. In addition to inhibiting 2OG oxygenases, fumarate modifies cysteine residues in multiple proteins to form S-(2-succinyl)-cysteine (2SC) and this chemical modification, termed succination, can have important functional consequences, such as the inactivation of glyceraldehyde-3-phosphate dehydrogenase in both an in vivo and in vitro setting [3]. Of potential clinical importance, we have reported recently that FH-deficient cells and tumors specifically exhibit high levels of 2SC that are absent in normal cells and tissues, thus providing a potential diagnostic biomarker and an alternative candidate or parallel mechanism for tumorigenesis [4]. In last month’s edition of Cancer Cell, we demonstrate through multiple genetic crosses in mice, that neither the presence of Hif, nor the absence of Phds, are required for renal cyst formation in an Fh1-deficient background and that surprisingly, loss of Hif-1α actually exacerbates the cystic phenotype [5]. Furthermore, we show that murine Fh1 deficient renal cysts, mouse embryonic fibroblasts