A Role for Cytosolic Fumarate Hydratase in Urea Cycle Metabolism and Renal Neoplasia
Julie Adam,
Ming Yang,
Christina Bauerschmidt,
Mitsuhiro Kitagawa,
Linda O’Flaherty,
Pratheesh Maheswaran,
Gizem Özkan,
Natasha Sahgal,
Dilair Baban,
Keiko Kato,
Kaori Saito,
Keiko Iino,
Kaori Igarashi,
Michael Stratford,
Christopher Pugh,
Daniel A. Tennant,
Christian Ludwig,
Benjamin Davies,
Peter J. Ratcliffe,
Mona El-Bahrawy,
Houman Ashrafian,
Tomoyoshi Soga,
Patrick J. Pollard
Affiliations
Julie Adam
Cancer Biology and Metabolism Group, Nuffield Department of Medicine, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UK
Ming Yang
Cancer Biology and Metabolism Group, Nuffield Department of Medicine, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UK
Christina Bauerschmidt
Cancer Biology and Metabolism Group, Nuffield Department of Medicine, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UK
Mitsuhiro Kitagawa
Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Tsuruoka, Yamagata 997-0052, Japan
Linda O’Flaherty
Cancer Biology and Metabolism Group, Nuffield Department of Medicine, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UK
Pratheesh Maheswaran
Cancer Biology and Metabolism Group, Nuffield Department of Medicine, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UK
Gizem Özkan
Cancer Biology and Metabolism Group, Nuffield Department of Medicine, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UK
Natasha Sahgal
Bioinformatics and Statistical Genetics, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
Dilair Baban
High Throughput Genomics, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
Keiko Kato
Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Tsuruoka, Yamagata 997-0052, Japan
Kaori Saito
Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Tsuruoka, Yamagata 997-0052, Japan
Keiko Iino
Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Tsuruoka, Yamagata 997-0052, Japan
Kaori Igarashi
Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Tsuruoka, Yamagata 997-0052, Japan
Michael Stratford
Gray Institute for Radiation Oncology and Biology, Department of Oncology, Old Road Campus Research Building, University of Oxford, Roosevelt Drive, Oxford OX3 7DQ, UK
Christopher Pugh
Hypoxia Biology Group, Nuffield Department of Medicine, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UK
Daniel A. Tennant
School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Christian Ludwig
School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Benjamin Davies
Transgenic Core, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
Peter J. Ratcliffe
Hypoxia Biology Group, Nuffield Department of Medicine, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UK
Mona El-Bahrawy
Department of Histopathology, Imperial College London, Hammersmith Hospital, London W12 0NN, UK
Houman Ashrafian
Department of Cardiovascular Medicine, University of Oxford, Oxford OX3 9DU, UK
Tomoyoshi Soga
Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Tsuruoka, Yamagata 997-0052, Japan
Patrick J. Pollard
Cancer Biology and Metabolism Group, Nuffield Department of Medicine, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UK
The identification of mutated metabolic enzymes in hereditary cancer syndromes has established a direct link between metabolic dysregulation and cancer. Mutations in the Krebs cycle enzyme, fumarate hydratase (FH), predispose affected individuals to leiomyomas, renal cysts, and cancers, though the respective pathogenic roles of mitochondrial and cytosolic FH isoforms remain undefined. On the basis of comprehensive metabolomic analyses, we demonstrate that FH1-deficient cells and tissues exhibit defects in the urea cycle/arginine metabolism. Remarkably, transgenic re-expression of cytosolic FH ameliorated both renal cyst development and urea cycle defects associated with renal-specific FH1 deletion in mice. Furthermore, acute arginine depletion significantly reduced the viability of FH1-deficient cells in comparison to controls. Our findings highlight the importance of extramitochondrial metabolic pathways in FH-associated oncogenesis and the urea cycle/arginine metabolism as a potential therapeutic target.
