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Fumarate Hydratase Deficiency in Renal Cancer Induces Glycolytic Addiction and Hypoxia-Inducible Transcription Factor 1α Stabilization by Glucose-Dependent Generation of Reactive Oxygen Species
Open accessAbstract
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an inherited cancer syndrome linked to biallelic inactivation of the gene encoding the tricarboxylic acid cycle enzyme fumarate hydratase (FH). Individuals with HLRCC are at risk to develop cutaneous and uterine leiomyomas and an aggressive form of kidney cancer. Pseudohypoxic drive-the aberrant activation of cellular hypoxia response pathways despite normal oxygen tension-is considered to be a likely mechanism underlying the etiology of this tumor. Pseudohypoxia requires the oxygen-independent stabilization of the alpha subunit of the hypoxia-inducible transcription factor (HIF-1alpha). Under normoxic conditions, proline hydroxylation of HIF-1alpha permits VHL recognition and subsequent targeting for proteasomal degradation. Here, we demonstrate that inactivating mutations of FH in an HLRCC-derived cell line result in glucose-mediated generation of cellular reactive oxygen species (ROS) and ROS-dependent HIF-1alpha stabilization. Additionally, we demonstrate that stable knockdown of FH in immortalized renal epithelial cells results in ROS-dependent HIF-1alpha stabilization. These data reveal that the obligate glycolytic switch present in HLRCC is critical to HIF stabilization via ROS generation.
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“Accumulation of reactive oxygen species, an independent trigger for HIF stabilization, may contribute to this process in some cases of defective SDH or FH (Guzy et al., 2008; Sudarshan et al., 2009).”
From Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? (2012) · cites this paper as Sudarshan et al., 2009
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Metadata
- Authors
- Sudarshan, S., Sourbier, C., Kong, H.-S., Block, K., Romero, V. A. V., Yang, Y., Galindo, C., Mollapour, M., Scroggins, B., Goode, N., Lee, M.-J., Gourlay, C. W., Trepel, J., Linehan, W. M., & Neckers, L.
- Affiliations
- National Institutes of Health (US)
- The University of Texas at San Antonio Health Science Center (US)
- Urologic Oncology Branch, National Cancer Institute, Bethesda, Maryland 20892
- University of Kent (GB)
- Corresponding author
- Neckers, Len
- ORCID
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2009-08-01
- Volume
- 29
- Issue
- 15
- Pages
- 4080-4090
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC2715796
- OpenAlex
- W2098189012
- Cited by
- 217
- References
- 43
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 8 · 2023: 8 · 2022: 9 · 2021: 13 · 2020: 11 · 2019: 15 · 2018: 13 · 2017: 10 · 2016: 14 · 2015: 15 · 2014: 12 · 2013: 16 · 2012: 31
- FWCI
- 7.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Kent Academic Repository (University of Kent) (submittedVersion)
- Funders
- Association for the Study of Animal Behaviour
- National Institutes of Health
- National Cancer Institute (R01CA131272, Z01SC006659, Z01BC010683)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Renal cell carcinoma treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
- Keywords
- fumarate hydratase deficiency, hereditary leiomyomatosis and renal cell carcinoma, HIF-1α stabilization, reactive oxygen species, pseudohypoxia, prolyl hydroxylation, VHL, renal cell carcinoma, TCA cycle, glucose metabolism
- MeSH terms
- Cell Line, Fumarate Hydratase, Glucose, Glycolysis, Humans, Kidney Neoplasms, Multienzyme Complexes, NADH, NADPH Oxidoreductases, Blotting, Western, Reactive Oxygen Species, Oxidative Stress, RNA Interference, Cell Line, Tumor, Protein Kinase C-delta, Hypoxia-Inducible Factor 1, alpha Subunit
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