Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1.
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.
Kim
Jung-whan
JW
Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Gao
Ping
P
Liu
Yen-Chun
YC
Semenza
Gregg L
GL
Dang
Chi V
CV
D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D004247:DNA / Q000378:metabolism; D004790:Enzyme Induction; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D006593:Hexokinase / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D009369:Neoplasms / Q000473:pathology; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012045:Regulatory Sequences, Nucleic Acid; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*