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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
Open accessAbstract
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.
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“To preferentially engage aerobic glycolysis, cancer cells frequently co-opt several pathways, including the HIF/hypoxia transcriptional program, to enhance PDK1 expression and achieve PDHC repression (142).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [142]
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Metadata
- Authors
- Kim, J.-W., Gao, P., Liu, Y.-C., Semenza, G. L., & Dang, C. V.
- Affiliations
- Division of Hematology, Department of Medicine
- Graduate Program of Pathobiology
- Johns Hopkins University (US)
- Corresponding author
- Dang, Chi V.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2007-11-01
- Volume
- 27
- Issue
- 21
- Pages
- 7381-7393
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC2169056
- OpenAlex
- W2105250121
- Cited by
- 658
- References
- 87
- Citations by year
- 2026: 21 · 2025: 29 · 2024: 28 · 2023: 31 · 2022: 49 · 2021: 60 · 2020: 45 · 2019: 48 · 2018: 38 · 2017: 36 · 2016: 38 · 2015: 28 · 2014: 44 · 2013: 29 · 2012: 35
- FWCI
- 8.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Johns Hopkins University
- National Institutes of Health (n01hv28180-13-0-0, NO1-HV-28180)
- National Heart, Lung, and Blood Institute (N01 HV028180, N02-HV-28180)
- National Cancer Institute (CA 57341, R01CA057341, CA52497)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Kruppel-like factors research
- Keywords
- HIF-1, c-Myc, vascular endothelial growth factor, hexokinase 2, pyruvate dehydrogenase kinase 1, Warburg effect, glycolysis, mitochondrial respiration, Burkitt lymphoma, tumor hypoxia, angiogenesis, cancer metabolism
- MeSH terms
- Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Cell Line, DNA, Enzyme Induction, Glucose, Glycolysis, Hexokinase, Humans, Neoplasms, Protein Binding, Regulatory Sequences, Nucleic Acid, Proto-Oncogene Proteins c-myc, Protein Serine-Threonine Kinases, Vascular Endothelial Growth Factor A, Chromatin Immunoprecipitation, Hypoxia-Inducible Factor 1
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