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J. Biol. Chem., Vol. 282, Issue 7, 4524-4532, February 16, 2007

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

POSSIBLE LINKS BETWEEN CELL METABOLISM AND STABILIZATION OF HIF^*

Peppi Koivunen^¶, Maija Hirsilä^¶, Anne M. Remes^||, Ilmo E. Hassinen^¶, Kari I. Kivirikko^¶, and Johanna Myllyharju^¶1

From the Collagen Research Unit, Biocenter Oulu, Departments of ^¶Medical Biochemistry and Molecular Biology and ^||Neurology, University of Oulu, FIN-90014 Oulu, Finland

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 µM and succinate 350–460 µM, whereas neither inhibited FIH. Oxaloacetate was an additional inhibitor of all three HIF-P4Hs with K_i values of 400–1000 µM and citrate of HIF-P4H-3, citrate being the most effective inhibitor of FIH with a K_i of 110 µM. Culturing of cells with fumarate diethyl or dimethyl ester, or a high concentration of monoethyl ester, stabilized HIF-1 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-s and effects on tumor pathology.

Received for publication, November 8, 2006

^* This work was supported by Grants 200471 and 202469 from the Health Science Council and 44843 from the Finnish Centre of Excellence Programme 2000–2005 of the Academy of Finland, the S. Juselius Foundation, and FibroGen Inc. (South San Francisco, CA). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: P. O. Box 5000, University of Oulu, FIN-90014 Oulu, Finland. Tel.: 358-8-537-5740; Fax: 358-8-537-5811; E-mail: johanna.myllyharju{at}oulu.fi.

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