The emerging role of fumarate as an oncometabolite

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.

[1]  M. Brosnan,et al.  Renal arginine metabolism. , 2004, The Journal of nutrition.

[2]  P. Carmeliet,et al.  Renal Cyst Formation in Fh1-Deficient Mice Is Independent of the Hif/Phd Pathway: Roles for Fumarate in KEAP1 Succination and Nrf2 Signaling , 2011, Cancer cell.

[3]  Chi V Dang,et al.  Cancer's molecular sweet tooth and the Warburg effect. , 2006, Cancer research.

[4]  Gurpreet W. Tang,et al.  Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes , 2009, Nature.

[5]  Bin Wang,et al.  Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. , 2011, Cancer cell.

[6]  Ximing J. Yang,et al.  An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. , 2011, Cancer cell.

[7]  L. Cantley,et al.  Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation , 2009, Science.

[8]  Alan J. Robinson,et al.  Fumarate Is Cardioprotective via Activation of the Nrf2 Antioxidant Pathway , 2012, Cell metabolism.

[9]  K. Clarke,et al.  Dysregulation of hypoxia pathways in fumarate hydratase-deficient cells is independent of defective mitochondrial metabolism. , 2010, Human molecular genetics.

[10]  Hui Yang,et al.  Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. , 2012, Genes & development.

[11]  M. McMahon,et al.  NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer. , 2009, Trends in biochemical sciences.

[12]  F. Ducray,et al.  IDH1 and IDH2 mutations in gliomas. , 2009, The New England journal of medicine.

[13]  M. Tomita,et al.  Differential Metabolomics Reveals Ophthalmic Acid as an Oxidative Stress Biomarker Indicating Hepatic Glutathione Consumption* , 2006, Journal of Biological Chemistry.

[14]  E. Boyland.  Metabolism of Tumours , 1940, Nature.

[15]  Scott E. Kern,et al.  Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis , 2011, Nature.

[16]  J. Stȩpiński,et al.  The purine nucleotide cycle activity in renal cortex and medulla. , 1989, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[17]  J R Griffiths,et al.  Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. , 2005, Human molecular genetics.

[18]  O. Pines,et al.  Mitochondrial and Cytosolic Isoforms of Yeast Fumarase Are Derivatives of a Single Translation Product and Have Identical Amino Termini* , 2001, Journal of Biological Chemistry.

[19]  T. Lyons,et al.  S-(2-Succinyl)cysteine: a novel chemical modification of tissue proteins by a Krebs cycle intermediate. , 2006, Archives of biochemistry and biophysics.

[20]  J. Baynes,et al.  Mitochondrial stress causes increased succination of proteins in adipocytes in response to glucotoxicity. , 2012, The Biochemical journal.

[21]  R. Klose,et al.  The oncometabolite 2‐hydroxyglutarate inhibits histone lysine demethylases , 2011, EMBO reports.

[22]  R. McLendon,et al.  IDH1 and IDH2 mutations in gliomas. , 2009, The New England journal of medicine.

[23]  J. Licht,et al.  Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. , 2010, Cancer cell.

[24]  Ian Tomlinson,et al.  Molecular and Cellular Pathobiology Expression Profiling in Progressive Stages of Fumarate- Hydratase Deficiency: the Contribution of Metabolic Changes to Tumorigenesis , 2022 .

[25]  E. Gottlieb,et al.  Cell-Permeating α-Ketoglutarate Derivatives Alleviate Pseudohypoxia in Succinate Dehydrogenase-Deficient Cells , 2007, Molecular and Cellular Biology.

[26]  Christian M. Metallo,et al.  Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia , 2011, Nature.

[27]  Omar Abdel-Wahab,et al.  The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. , 2010, Cancer cell.

[28]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[29]  L. Aravind,et al.  Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2 , 2010, Nature.

[30]  P. Carmeliet,et al.  Renal cyst formation in Fh 1-deficient mice is independent of the Hif / Phd pathway , 2011 .

[31]  S. Berger,et al.  IDH mutation impairs histone demethylation and results in a block to cell differentiation , 2012, Nature.

[32]  A. Paetau,et al.  Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer , 2002, Nature Genetics.

[33]  R. Deberardinis,et al.  Beyond aerobic glycolysis: Transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis , 2007, Proceedings of the National Academy of Sciences.

[34]  N. Oldham,et al.  Structural and Mechanistic Studies on the Inhibition of the Hypoxia-inducible Transcription Factor Hydroxylases by Tricarboxylic Acid Cycle Intermediates* , 2007, Journal of Biological Chemistry.

[35]  D. Busam,et al.  An Integrated Genomic Analysis of Human Glioblastoma Multiforme , 2008, Science.

[36]  O. Warburg.  [Origin of cancer cells]. , 1956, Oncologia.

[37]  M. Tomita,et al.  Quantitative metabolome analysis using capillary electrophoresis mass spectrometry. , 2003, Journal of proteome research.

[38]  G. Semenza.  A return to cancer metabolism , 2011, Journal of Molecular Medicine.

[39]  W. Marston Linehan,et al.  Reductive carboxylation supports growth in tumor cells with defective mitochondria , 2011, Nature.

[40]  Gabriela Kalna,et al.  Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase , 2011, Nature.

[41]  Donna D. Zhang.  The Nrf2-Keap1-ARE signaling pathway: The regulation and dual function of Nrf2 in cancer. , 2010, Antioxidants & redox signaling.

[42]  Otto Warburn,et al.  THE METABOLISM OF TUMORS , 1931 .

[43]  Y. Peleg,et al.  The single translation product of the FUM1 gene (fumarase) is processed in mitochondria before being distributed between the cytosol and mitochondria in Saccharomyces cerevisiae , 1994, Molecular and cellular biology.

[44]  Ken Chen,et al.  Recurring mutations found by sequencing an acute myeloid leukemia genome. , 2009, The New England journal of medicine.

[45]  J. Baynes,et al.  Succination of proteins in diabetes , 2011, Free radical research.

[46]  Bin Tean Teh,et al.  Somatic mutations of the histone H3K27 demethylase, UTX, in human cancer , 2009, Nature Genetics.

[47]  O. Warburg,et al.  THE METABOLISM OF TUMORS IN THE BODY , 1927, The Journal of general physiology.

[48]  J. Baynes,et al.  Succination of Thiol Groups in Adipose Tissue Proteins in Diabetes , 2009, The Journal of Biological Chemistry.

[49]  Eyal Gottlieb,et al.  Inborn and acquired metabolic defects in cancer , 2011, Journal of Molecular Medicine.

[50]  Alison Martin,et al.  Targeted inactivation of fh1 causes proliferative renal cyst development and activation of the hypoxia pathway. , 2007, Cancer cell.

[51]  G. Semenza,et al.  'The metabolism of tumours': 70 years later. , 2001, Novartis Foundation symposium.

[52]  L. Aaltonen,et al.  Aberrant succination of proteins in fumarate hydratase‐deficient mice and HLRCC patients is a robust biomarker of mutation status , 2011, The Journal of pathology.

[53]  J. Baynes,et al.  Inactivation of Glyceraldehyde-3-Phosphate Dehydrogenase by Fumarate in Diabetes , 2008, Diabetes.

[54]  M. McMahon,et al.  Keap1 perceives stress via three sensors for the endogenous signaling molecules nitric oxide, zinc, and alkenals , 2010, Proceedings of the National Academy of Sciences.

[55]  Yuen-Li Chung,et al.  HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. , 2005, Cancer cell.

[56]  D. Gilliland,et al.  Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. , 2009, Blood.

[57]  Masaru Tomita,et al.  Systems Biology, Metabolomics, and Cancer Metabolism , 2012, Science.

[58]  Mark T. Waters,et al.  This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits distribution,andreproductioninanymedium,providedtheoriginalauthorandsourcearecredited.Thislicensedoesnot permit commercial exploitation or the creation of derivative works without sp , 2009 .

[59]  Eyal Gottlieb,et al.  Mitochondrial tumour suppressors: a genetic and biochemical update , 2005, Nature Reviews Cancer.

[60]  E. Shaulian,et al.  Fumarase: A Mitochondrial Metabolic Enzyme and a Cytosolic/Nuclear Component of the DNA Damage Response , 2010, PLoS biology.

[61]  C. Rock,et al.  Cancer-associated Isocitrate Dehydrogenase Mutations Inactivate NADPH-dependent Reductive Carboxylation* , 2012, The Journal of Biological Chemistry.

[62]  W. Linehan,et al.  Fumarate Hydratase Deficiency in Renal Cancer Induces Glycolytic Addiction and Hypoxia-Inducible Transcription Factor 1α Stabilization by Glucose-Dependent Generation of Reactive Oxygen Species , 2009, Molecular and Cellular Biology.