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.
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FH deletion renders mouse and human cells more sensitive to genetic and pharmacological inhibition of heme oxygenase 1.
“Consequently, FH deletion renders mouse and human cells more sensitive to genetic and pharmacological inhibition of heme oxygenase 1 (Hmox1), an enzyme involved in heme degradation.”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Frezza et al., 2011
FH and SDH mutations create truncal metabolic aberrations, induce permanent restructuring of the TCA cycle, and result in numerous metabolic liabilities in preclinical models.
“FH and SDH mutations also create truncal metabolic aberrations. These mutations induce permanent restructuring of the TCA cycle and result in numerous metabolic liabilities in preclinical models (106–108).”
From Metabolic reprogramming and cancer progression (2020) · cites this paper as [106]
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- Authors
- Frezza, C., Zheng, L., Folger, O., Rajagopalan, K. N., MacKenzie, E. D., Jerby, L., Micaroni, M., Chaneton, B., Adam, J., Hedley, A., Kalna, G., Tomlinson, I. P. M., Pollard, P. J., Watson, D. G., Deberardinis, R. J., Shlomi, T., Ruppin, E., & Gottlieb, E.
- Affiliations
- Cancer Research UK Scotland Institute (GB)
- Tel Aviv University (IL)
- The University of Texas Southwestern Medical Center (US)
- The University of Queensland (AU)
- University of Oxford (GB)
- Centre for Human Genetics (GB)
- University of Strathclyde (GB)
- Technion – Israel Institute of Technology (IL)
- Corresponding author
- Gottlieb, Eyal
- ORCID
- Venue
- Nature
- Published
- 2011-08-17
- Volume
- 477
- Issue
- 7363
- Pages
- 225-228
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2036181747
- Cited by
- 503
- References
- 25
- Citations by year
- 2026: 13 · 2025: 18 · 2024: 28 · 2023: 25 · 2022: 52 · 2021: 16 · 2020: 31 · 2019: 32 · 2018: 31 · 2017: 40 · 2016: 32 · 2015: 44 · 2014: 47 · 2013: 50 · 2012: 38
- FWCI
- 15.45
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Strathprints: The University of Strathclyde institutional repository (University of Strathclyde) (submittedVersion)
- Funders
- Wellcome Trust (WT091112MA, 090532)
- Cancer Research UK
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (K08DK072565, DK072565-05)
- Division of Materials Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- fumarate hydratase, heme oxygenase, synthetic lethality, fumarate hydratase deficiency, hereditary leiomyomatosis and renal cell carcinoma, kidney cancer, glutamine metabolism, bilirubin, heme biosynthesis, TCA cycle, hypoxia-inducible factor, metabolic pathways, therapeutic target
- MeSH terms
- Animals, Bilirubin, Cell Line, Cells, Cultured, Citric Acid Cycle, Computer Simulation, Fumarate Hydratase, Fumarates, Genes, Lethal, Glutamine, Heme, Heme Oxygenase (Decyclizing), Kidney Neoplasms, Mitochondria, Mutation, NAD, Neoplastic Syndromes, Hereditary, Skin Neoplasms, Uterine Neoplasms, Genes, Tumor Suppressor, Leiomyomatosis, Mice
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