The DOI matches its Crossref record; 62 of the 63 references it cites were found in a registry or an index.
HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: Novel role of fumarate in regulation of HIF stability
Open accessAbstract
Individuals with hemizygous germline fumarate hydratase (FH) mutations are predisposed to renal cancer. These tumors predominantly exhibit functional inactivation of the remaining wild-type allele, implicating FH inactivation as a tumor-promoting event. Hypoxia-inducible factors are expressed in many cancers and are increased in clear cell renal carcinomas. Under normoxia, the HIFs are labile due to VHL-dependent proteasomal degradation, but stabilization occurs under hypoxia due to inactivation of HIF prolyl hydroxylase (HPH), which prevents HIF hydroxylation and VHL recognition. We demonstrate that FH inhibition, together with elevated intracellular fumarate, coincides with HIF upregulation. Further, we show that fumarate acts as a competitive inhibitor of HPH. These data delineate a novel fumarate-dependent pathway for regulating HPH activity and HIF protein levels.
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In the citing paper
“In addition to requiring 2-oxoglutarate as a cosubstrate, the HIF hydroxylases have been reported to be inhibited by citrate, isocitrate, succinate, fumarate, malate, oxaloacetate, and pyruvate (Dalgard et al., 2004; Hewitson et al., 2007; Isaacs et al., 2005; Koivunen et al., 2007a; Selak et al., 2005).”
From Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. (2008) · cites this paper as Isaacs et al., 2005
In the citing paper
“To date, the clearest evidence that metabolites modulate HIF signaling comes from cells that are genetically defective in fumarate hydratase (FH) (Isaacs et al., 2005) or succinate hydrogenase (SDH; subunits b, c, and d) (MacKenzie et al., 2007; Pollard et al., 2005; Selak et al., 2005).”
From Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. (2008) · cites this paper as Isaacs et al., 2005
In the citing paper
“Similar to succinate, fumarate contributes to the inactivation of PHD, stabilizing HIF proteins to promote cell survival133”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [133]
In the citing paper
“For example, the HIF1α transcription factor accumulates in SDH and FH mutant tumors, presumably due to inhibition of the EglN prolyl hydroxylases (Dahia et al., 2005; Isaacs et al., 2005; Pollard et al., 2005, 2007; Selak et al., 2005).”
From Influence of Metabolism on Epigenetics and Disease (2013) · cites this paper as Isaacs et al., 2005
In the citing paper
“A similar model of substrate-mediated PHD inhibition has been described (23, 37, 42) in which the loss of fumarate hydratase activity leads to the accumulation of fumarate, which also can inhibit PHD competitively.”
From Loss of the SdhB, but Not the SdhA, Subunit of Complex II Triggers Reactive Oxygen Species-Dependent Hypoxia-Inducible Factor Activation and Tumorigenesis (2008) · cites this paper as [23]
In the citing paper
“PHDs are inactive at low O2 and can be inactivated by the accumulation of TCA metabolites fumarate and succinate, which may occur from mutations in the tumor suppressor genes succinate dehydrogenase subunit B or fumarate hydratase (187, 334, 384).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [187]
In the citing paper
“In addition to affecting the activity of chromatin-associated αKG-dependent dioxygenases, succinate and fumarate accumulation can also inhibit αKG-dependent prolyl hydroxylases, leading to stabilization of HIF-1 and concomitant activation of the HIF/hypoxia transcriptional program (184, 185).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [184]
In the citing paper
“High levels of succinate and fumarate can inhibit PHD2 activity through product-mediated inhibition of PHD function, leading to HIF-1α protein stabilization under normoxic (20% O2) conditions (100, 101).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [100]
In the citing paper
“Subsequent work confirmed that fumarate could inhibit PHD2 (Isaacs et al., 2005)”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Isaacs et al., 2005
In the citing paper
“elevated levels of succinate or fumarate can inhibit PHD activity [65, 66]”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [65]
In the citing paper
“Both succinate and fumarate are competitive PHD inhibitors, and the massive accumulation of these metabolites in cells lacking SDH or FH activity elicit a hypoxic response even under oxygen-replete condition (Isaacs et al., 2005; Selak et al., 2005).”
From Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? (2012) · cites this paper as Isaacs et al., 2005
In the citing paper
“Furthermore, both succinate and fumarate aberrantly increase the function of hypoxia inducible factors (HIFs).”
From Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? (2012) · cites this paper as Isaacs et al., 2005
In the citing paper
“In the case of D2HGA, about 50% of patients present with D2HGDH mutations, while the remaining half possess mutations in the Krebs cycle enzyme isocitrate dehydrogenase 2 (IDH2), which converts isocitrate to α-KG110.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [110]
Citations
Cites
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Targeting HIF-1 for cancer therapy
Semenza, G. L. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1187 · Cited by 6,717
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Self-citationThe tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis
Maxwell, P. H., Wiesener, M. S., Chang, G.-W., Clifford, S. C., Vaux, E. C., Cockman, M. E., Wykoff, C. C., Pugh, C. W., Maher, E. R., & Ratcliffe, P. J. (1999) · Nature · doi:10.1038/20459 · Cited by 5,180
Self-citationHIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O 2 Sensing
Ivan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., Salic, A., Asara, J. M., Lane, W. S., & Kaelin Jr., W. G. (2001) · Science · doi:10.1126/science.1059817 · Cited by 4,735
Epstein, A. C. R., Gleadle, J. M., McNeill, L. A., Hewitson, K. S., O'Rourke, J., Mole, D. R., Mukherji, M., Metzen, E., Wilson, M. I., Dhanda, A., et al. (2001) · Cell · doi:10.1016/s0092-8674(01)00507-4 · Cited by 3,333
Self-citationA conserved family of prolyl-4-hydroxylases that modify HIF
Bruick, R. K., & McKnight, S. L. (2001) · Science · doi:10.1126/science.1066373 · Cited by 2,549
Cellular and developmental control of O 2 homeostasis by hypoxia-inducible factor 1α
Iyer, N. V., Kotch, L. E., Agani, F., Leung, S. W., Laughner, E., Wenger, R. H., Gassmann, M., Gearhart, J. D., Lawler, A. M., Yu, A. Y., et al. (1998) · Genes & Development · doi:10.1101/gad.12.2.149 · Cited by 2,476
(1999) · PubMed · Cited by 2,204
Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase
Selak, M. A., Armour, S. M., MacKenzie, E. D., Boulahbel, H., Watson, D. G., Mansfield, K. D., Pan, Y., Simon, M. C., Thompson, C. B., & Gottlieb, E. (2005) · Cancer Cell · doi:10.1016/j.ccr.2004.11.022 · Cited by 2,108 · cited 3×
“Succinate also upregulates HIF by inhibiting its proline hydroxylation (Selak et al., 2005), but in vitro enzyme kinetic analysis proves it to be a weaker antagonist of 2-OG, a finding in keeping with its reduced potency (relative to fumarate) in causing intracellular HIF accumulation in A549 cells.”
BackgroundInfluential
Cited by
Sorted by citations
The Biology of Cancer: Metabolic Reprogramming Fuels Cell Growth and Proliferation
DeBerardinis, R. J., Lum, J. J., Hatzivassiliou, G., & Thompson, C. B. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2007.10.002 · Cited by 4,088
Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway.
Kaelin, W. G., & Ratcliffe, P. J. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.04.009 · Cited by 3,251
Self-citationMetabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate
Ward, P. S., & Thompson, C. B. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.02.014 · Cited by 3,233
Mitochondrial TCA cycle metabolites control physiology and disease
Martínez-Reyes, I., & Chandel, N. S. (2020) · Nature Communications · doi:10.1038/s41467-019-13668-3 · Cited by 2,813
Xu, W., Yang, H., Liu, Y., Yang, Y., Wang, P., Kim, S.-H., Ito, S., Yang, C., Wang, P., Xiao, M.-T., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2010.12.014 · Cited by 2,875
Metadata
- Authors
- Isaacs, J. S., Jung, Y. J., Mole, D. R., Lee, S., Torres-Cabala, C., Chung, Y.-L., Merino, M., Trepel, J., Zbar, B., Toro, J., Ratcliffe, P. J., Linehan, W. M., & Neckers, L.
- Affiliations
- National Institutes of Health (US)
- Pusan National University (KR)
- University of Oxford (GB)
- National Cancer Institute (US)
- St George's Hospital (GB)
- Corresponding author
- Neckers, Len
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2005-08
- Volume
- 8
- Issue
- 2
- Pages
- 143-153
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2059747280
- Semantic Scholar
- 6906ef0c1fe45571640c3c7a6b3c9c2d9a979a64
- Cited by
- 958
- References
- 63
- Citations by year
- 2026: 26 · 2025: 30 · 2024: 30 · 2023: 36 · 2022: 45 · 2021: 37 · 2020: 46 · 2019: 40 · 2018: 50 · 2017: 40 · 2016: 44 · 2015: 64 · 2014: 54 · 2013: 60 · 2012: 64
- FWCI
- 14.76
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- 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, hypoxia-inducible factor, fumarate, HIF prolyl hydroxylase, competitive inhibition, clear cell renal cell carcinoma, biallelic loss, cancer susceptibility, hypoxia
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Adult, Alleles, Carcinoma, Renal Cell, DNA-Binding Proteins, Female, Fumarate Hydratase, Fumarates, Humans, Ketoglutaric Acids, Kidney Neoplasms, Male, Middle Aged, Nuclear Proteins, Procollagen-Proline Dioxygenase, Syndrome, Transcription Factors, Up-Regulation, Gene Expression Regulation, Neoplastic, Leiomyomatosis, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit
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