Jung-whan Kim^1,‡, Ping Gao¹, Yen-Chun Liu², Gregg L. Semenza^1,3,4,5 and Chi V. Dang^1,2,3,*

¹Division of Hematology, Department of Medicine
²Graduate Program of Pathobiology
³Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
⁴Institute for Cell Engineering
⁵Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

^*Corresponding author. Mailing address: Ross Research Building, Room 1032, 720 Rutland Avenue, Baltimore, MD 21205.
^‡ Present address: Department of Anatomy, University of California, San Francisco, HSW 1301, 513 Parnassus Ave., San Francisco, CA 94131.

ABSTRACT
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.