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Hypoxia-Inducible Factor 1 and Dysregulated c-Myc Cooperatively Induce Vascular Endothelial Growth Factor and Metabolic Switches Hexokinase 2 and Pyruvate Dehydrogenase Kinase 1 ^,

Jung-whan Kim,^1, Ping Gao,¹ Yen-Chun Liu,² Gregg L. Semenza,^1,3,4,5 and Chi V. Dang^1,2,3*

Division of Hematology, Department of Medicine,¹ Graduate Program of Pathobiology,² Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins,³ Institute for Cell Engineering,⁴ Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205⁵

Received 14 March 2007/ Returned for modification 24 April 2007/ Accepted 24 August 2007

Hypoxia is a pervasive microenvironmental factor that affects normal development as well as tumor progression. In most normal cells, hypoxia stabilizes hypoxia-inducible transcription factors (HIFs), particularly HIF-1, which activates genes involved in anaerobic metabolism and angiogenesis. As hypoxia signals a cellular deprivation state, HIF-1 has also been reported to counter the activity of MYC, which encodes a transcription factor that drives cell growth and proliferation. Since many human cancers express dysregulated MYC, we sought to determine whether HIF-1 would in fact collaborate with dysregulated MYC rather countering its function. Here, using the P493-6 Burkitt's lymphoma model with an inducible MYC, we demonstrate that HIF-1 cooperates with dysregulated c-Myc to promote glycolysis by induction of hexokinase 2, which catalyzes the first step of glycolysis, and pyruvate dehydrogenase kinase 1, which inactivates pyruvate dehydrogenase and diminishes mitochondrial respiration. We also found the collaborative induction of vascular endothelial growth factor (VEGF) by HIF-1 and dysregulated c-Myc. This study reports the previously unsuspected collaboration between HIF-1 and dysregulated MYC and thereby provides additional insights into the regulation of VEGF and the Warburg effect, which describes the propensity for cancer cells to convert glucose to lactate.

Published ahead of print on 4 September 2007.

Supplemental material for this article may be found at http://mcb.asm.org/.

Present address: Department of Anatomy, University of California, San Francisco, HSW 1301, 513 Parnassus Ave., San Francisco, CA 94131.

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