Cited by 521Cancer, Hypoxia, and MetabolismErythropoietin and Anemia TreatmentMetal-Catalyzed Oxygenation Mechanisms

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Inhibition of Hypoxia-inducible Factor (HIF) Hydroxylases by Citric Acid Cycle Intermediates

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Koivunen, Peppi, Hirsilä, Maija, Remes, Anne M., Hassinen, Ilmo E., Kivirikko, Kari I., Myllyharju, Johanna·2007·Journal of Biological Chemistry

DOI 10.1074/jbc.m610415200

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Abstract

The stability and transcriptional activity of the hypoxia-inducible factors (HIFs) are regulated by two oxygen-dependent events that are catalyzed by three HIF prolyl 4-hydroxylases (HIF-P4Hs) and one HIF asparaginyl hydroxylase (FIH). We have studied possible links between metabolic pathways and HIF hydroxylases by analyzing the abilities of citric acid cycle intermediates to inhibit purified human HIF-P4Hs and FIH. Fumarate and succinate were identified as in vitro inhibitors of all three HIF-P4Hs, fumarate having K(i) values of 50-80 microM and succinate 350-460 microM, whereas neither inhibited FIH. Oxaloacetate was an additional inhibitor of all three HIF-P4Hs with K(i) values of 400-1000 microM and citrate of HIF-P4H-3, citrate being the most effective inhibitor of FIH with a K(i) of 110 microM. Culturing of cells with fumarate diethyl or dimethyl ester, or a high concentration of monoethyl ester, stabilized HIF-1alpha and increased production of vascular endothelial growth factor and erythropoietin. Similar, although much smaller, changes were found in cultured fibroblasts from a patient with fumarate hydratase (FH) deficiency and upon silencing FH using small interfering RNA. No such effects were seen upon culturing of cells with succinate diethyl or dimethyl ester. As FIH was not inhibited by fumarate, our data indicate that the transcriptional activity of HIF is quite high even when binding of the coactivator p300 is prevented. Our data also support recent suggestions that the increased fumarate and succinate levels present in the FH and succinate dehydrogenase-deficient tumors, respectively, can inhibit the HIF-P4Hs with consequent stabilization of HIF-alphas and effects on tumor pathology.

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Authors: Koivunen, P., Hirsilä, M., Remes, A. M., Hassinen, I. E., Kivirikko, K. I., & Myllyharju, J.
Affiliations: University of Oulu (FI)
Corresponding author: Myllyharju, Johanna
ORCID: Koivunen, Peppi
Myllyharju, Johanna
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2007-02
Volume: 282
Issue: 7
Pages: 4524-4532
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.m610415200
OpenAlex: W2004183689
Semantic Scholar: c3ddd6b07c5b433f324955c53930fb199e6ecc2a
Cited by: 521
References: 43
Citations by year: 2026: 15 · 2025: 17 · 2024: 23 · 2023: 23 · 2022: 23 · 2021: 39 · 2020: 25 · 2019: 38 · 2018: 25 · 2017: 28 · 2016: 29 · 2015: 33 · 2014: 29 · 2013: 36 · 2012: 32
FWCI: 7.09
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 4997 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
Keywords: hypoxia-inducible factor, FIH, citric acid cycle intermediates, fumarate, succinic acid, oxaloacetate, citrate, fumarate hydratase deficiency, succinate dehydrogenase deficiency, HIF-1α stabilization, vascular endothelial growth factor, erythropoietin, p300 coactivator, cancer metabolism
MeSH terms: Cell Line, Citric Acid Cycle, Dose-Response Relationship, Drug, Enzyme Inhibitors, Erythropoietin, Fibroblasts, Fumarate Hydratase, Mixed Function Oxygenases, Neoplasms, Procollagen-Proline Dioxygenase, Succinate Dehydrogenase, Transcription, Genetic, Gene Expression Regulation, Enzymologic, Vascular Endothelial Growth Factor A, p300-CBP Transcription Factors, Hypoxia-Inducible Factor 1, alpha Subunit

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Inhibition of Hypoxia-inducible Factor (HIF) Hydroxylases by Citric Acid Cycle Intermediates

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