title: Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase.
abstract: Fumarate hydratase (FH) is an enzyme of the tricarboxylic acid cycle (TCA cycle) that catalyses the hydration of fumarate into malate. Germline mutations of FH are responsible for hereditary leiomyomatosis and renal-cell cancer (HLRCC). It has previously been demonstrated that the absence of FH leads to the accumulation of fumarate, which activates hypoxia-inducible factors (HIFs) at normal oxygen tensions. However, so far no mechanism that explains the ability of cells to survive without a functional TCA cycle has been provided. Here we use newly characterized genetically modified kidney mouse cells in which Fh1 has been deleted, and apply a newly developed computer model of the metabolism of these cells to predict and experimentally validate a linear metabolic pathway beginning with glutamine uptake and ending with bilirubin excretion from Fh1-deficient cells. This pathway, which involves the biosynthesis and degradation of haem, enables Fh1-deficient cells to use the accumulated TCA cycle metabolites and permits partial mitochondrial NADH production. We predicted and confirmed that targeting this pathway would render Fh1-deficient cells non-viable, while sparing wild-type Fh1-containing cells. This work goes beyond identifying a metabolic pathway that is induced in Fh1-deficient cells to demonstrate that inhibition of haem oxygenation is synthetically lethal when combined with Fh1 deficiency, providing a new potential target for treating HLRCC patients.
authors.affiliation: Cancer Research UK, Beatson Institute for Cancer Research, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: Frezza
authors.forename: Liang
authors.initials: L
authors.lastname: Zheng
authors.forename: Ori
authors.initials: O
authors.lastname: Folger
authors.forename: Kartik N
authors.initials: KN
authors.lastname: Rajagopalan
authors.forename: Elaine D
authors.initials: ED
authors.lastname: MacKenzie
authors.forename: Livnat
authors.initials: L
authors.lastname: Jerby
authors.forename: Massimo
authors.initials: M
authors.lastname: Micaroni
authors.forename: Barbara
authors.initials: B
authors.lastname: Chaneton
authors.forename: Julie
authors.initials: J
authors.lastname: Adam
authors.forename: Ann
authors.initials: A
authors.lastname: Hedley
authors.forename: Gabriela
authors.initials: G
authors.lastname: Kalna
authors.forename: Ian P M
authors.initials: IP
authors.lastname: Tomlinson
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Pollard
authors.forename: Dave G
authors.initials: DG
authors.lastname: Watson
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: Deberardinis
authors.forename: Tomer
authors.initials: T
authors.lastname: Shlomi
authors.forename: Eytan
authors.initials: E
authors.lastname: Ruppin
authors.forename: Eyal
authors.initials: E
authors.lastname: Gottlieb
mesh_terms: D000818:Animals; D001663:Bilirubin / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D002952:Citric Acid Cycle; D003198:Computer Simulation; D005649:Fumarate Hydratase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D005650:Fumarates / Q000378:metabolism; D005804:Genes, Lethal / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D005973:Glutamine / Q000378:metabolism; D006418:Heme / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D018231:Leiomyomatosis / Q000151:congenital / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009243:NAD / Q000378:metabolism; D009386:Neoplastic Syndromes, Hereditary; D012878:Skin Neoplasms; D014594:Uterine Neoplasms
chemical_list: D005650:Fumarates; D005973:Glutamine; D009243:NAD; D006418:Heme; C032005:fumaric acid; D006419:Heme Oxygenase (Decyclizing); D005649:Fumarate Hydratase; D001663:Bilirubin