The emerging role of fumarate as an oncometabolite
- 1 Henry Wellcome Building for Molecular Physiology, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- 2 Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan
- 3 Oxford-Keio Metabolomics Consortium, Oxford, UK
- 4 Oxford-Keio Metabolomics Consortium, Tsuruoka, Japan
The drive to understand how altered cellular metabolism and cancer are linked has caused a paradigm shift in the focus of cancer research. The discovery of a mutated metabolic enzyme, isocitrate dehydrogenase 1, that leads to accumulation of the oncometabolite 2-hydroxyglutarate, provided significant direct evidence that dysfunctional metabolism plays an important role in oncogenesis. Striking parallels exist with the Krebs cycle enzyme fumarate hydratase (FH), a tumor suppressor, whose mutation is associated with the development of leiomyomata, renal cysts, and tumors. Loss of FH enzymatic activity results in accumulation of intracellular fumarate which has been proposed to act as a competitive inhibitor of 2-oxoglutarate-dependent oxygenases including the hypoxia-inducible factor (HIF) hydroxylases, thus activating oncogenic HIF pathways. Interestingly, our studies have questioned the role of HIF and have highlighted other candidate mechanisms, in particular the non-enzymatic modification of cysteine residues (succination) that could lead to disruption or loss of protein functions, dysfunctional cell metabolism and cell signaling. Here, we discuss the evidence for proposing fumarate as an onco-metabolite.
Keywords: fumarate, oncometabolite, succination, dysregulated metabolism, mitochondrial dysfunction
Citation: Yang M, Soga T, Pollard PJ and Adam J (2012) The emerging role of fumarate as an oncometabolite. Front. Oncol. 2:85. doi: 10.3389/fonc.2012.00085
Received: 01 July 2012; Accepted: 16 July 2012;
Published online: 31 July 2012.
, Institut National de la Santé et de la Recherche Medicale, France
Copyright: © 2012 Yang, Soga, Pollard and Adam. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.
*Correspondence: Patrick J. Pollard, Henry Wellcome Building for Molecular Physiology, Nuffield Department of Medicine, University of Oxford, Oxford, UK. e-mail: firstname.lastname@example.org