HIF and C-Myc: Sibling Rivals for Control of Cancer Cell Metabolism and Proliferation

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2007 Aug 19

PMID 17692803

Citations 417

Authors

John D Gordan

Craig B Thompson

M Celeste Simon

Affiliations

Soon will be listed here.

Abstract

O(2) deprivation (hypoxia) and cellular proliferation engage opposite cellular pathways, yet often coexist during tumor growth. The ability of cells to grow during hypoxia results in part from crosstalk between hypoxia-inducible factors (HIFs) and the proto-oncogene c-Myc. Acting alone, HIF and c-Myc partially regulate complex adaptations undertaken by tumor cells growing in low O(2). However, acting in concert these transcription factors reprogram metabolism, protein synthesis, and cell cycle progression, to "fine tune" adaptive responses to hypoxic environments.

Citing Articles

Harnessing transcriptional regulation of alternative end-joining to predict cancer treatment.

Espin R, Medina-Jover F, Siguenza-Andrade J, Farran-Matas S, Mateo F, Figueras A NAR Cancer. 2025; 7(1):zcaf007.

PMID: 40061566 PMC: 11886861. DOI: 10.1093/narcan/zcaf007.

Regulatory role and therapeutic prospect of lactate modification in cancer.

Sun M, Wang K, Lu F, Yu D, Liu S Front Pharmacol. 2025; 16:1508552.

PMID: 40034817 PMC: 11872897. DOI: 10.3389/fphar.2025.1508552.

Adaptation of Natural Killer Cells to Hypoxia: A Review of the Transcriptional, Translational, and Metabolic Processes.

Chang T, Chen Y, Luo J, Zhang C, Chen S, Lin Z Immunotargets Ther. 2025; 14:99-121.

PMID: 39990274 PMC: 11846490. DOI: 10.2147/ITT.S492334.

Roles of Post-Translational Modifications of Transcription Factors Involved in Breast Cancer Hypoxia.

Seymour L, Nuru N, Johnson K, Gutierrez J, Njoku V, Darie C Molecules. 2025; 30(3).

PMID: 39942749 PMC: 11820228. DOI: 10.3390/molecules30030645.

FOSL1 transcriptionally dictates the Warburg effect and enhances chemoresistance in triple-negative breast cancer.

Zhao G, Liu Y, Yin S, Cao R, Zhao Q, Fu Y J Transl Med. 2025; 23(1):1.

PMID: 39748430 PMC: 11697476. DOI: 10.1186/s12967-024-06014-9.

References

Nilsson J, Keller U, Baudino T, Yang C, Norton S, Old J . Targeting ornithine decarboxylase in Myc-induced lymphomagenesis prevents tumor formation. Cancer Cell. 2005; 7(5):433-44. DOI: 10.1016/j.ccr.2005.03.036. View

Gordan J, Bertout J, Hu C, Diehl J, Simon M . HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell. 2007; 11(4):335-47. PMC: 3145406. DOI: 10.1016/j.ccr.2007.02.006. View

Raval R, Lau K, Tran M, Sowter H, Mandriota S, Li J . Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma. Mol Cell Biol. 2005; 25(13):5675-86. PMC: 1157001. DOI: 10.1128/MCB.25.13.5675-5686.2005. View

Li F, Wang Y, Zeller K, Potter J, Wonsey D, ODonnell K . Myc stimulates nuclearly encoded mitochondrial genes and mitochondrial biogenesis. Mol Cell Biol. 2005; 25(14):6225-34. PMC: 1168798. DOI: 10.1128/MCB.25.14.6225-6234.2005. View

Adhikary S, Eilers M . Transcriptional regulation and transformation by Myc proteins. Nat Rev Mol Cell Biol. 2005; 6(8):635-45. DOI: 10.1038/nrm1703. View

Bauer D, Hatzivassiliou G, Zhao F, Andreadis C, Thompson C . ATP citrate lyase is an important component of cell growth and transformation. Oncogene. 2005; 24(41):6314-22. DOI: 10.1038/sj.onc.1208773. View

Corn P, Ricci M, Scata K, Arsham A, Simon M, Dicker D . Mxi1 is induced by hypoxia in a HIF-1-dependent manner and protects cells from c-Myc-induced apoptosis. Cancer Biol Ther. 2005; 4(11):1285-94. DOI: 10.4161/cbt.4.11.2299. View

Liu L, Cash T, Jones R, Keith B, Thompson C, Simon M . Hypoxia-induced energy stress regulates mRNA translation and cell growth. Mol Cell. 2006; 21(4):521-31. PMC: 3153113. DOI: 10.1016/j.molcel.2006.01.010. View

Covello K, Kehler J, Yu H, Gordan J, Arsham A, Hu C . HIF-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes Dev. 2006; 20(5):557-70. PMC: 1410808. DOI: 10.1101/gad.1399906. View

10.

OHagan R, Schreiber-Agus N, Chen K, David G, Engelman J, Schwab R . Gene-target recognition among members of the myc superfamily and implications for oncogenesis. Nat Genet. 2000; 24(2):113-9. DOI: 10.1038/72761. View

11.

Coller H, Grandori C, Tamayo P, Colbert T, Lander E, Eisenman R . Expression analysis with oligonucleotide microarrays reveals that MYC regulates genes involved in growth, cell cycle, signaling, and adhesion. Proc Natl Acad Sci U S A. 2000; 97(7):3260-5. PMC: 16226. DOI: 10.1073/pnas.97.7.3260. View

12.

Osthus R, Shim H, Kim S, Li Q, Reddy R, Mukherjee M . Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J Biol Chem. 2000; 275(29):21797-800. DOI: 10.1074/jbc.C000023200. View

13.

Wykoff C, Beasley N, Watson P, Turner K, Pastorek J, Sibtain A . Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res. 2001; 60(24):7075-83. View

14.

Wonsey D, Zeller K, Dang C . The c-Myc target gene PRDX3 is required for mitochondrial homeostasis and neoplastic transformation. Proc Natl Acad Sci U S A. 2002; 99(10):6649-54. PMC: 124457. DOI: 10.1073/pnas.102523299. View

15.

Vafa O, Wade M, Kern S, Beeche M, Pandita T, Hampton G . c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: a mechanism for oncogene-induced genetic instability. Mol Cell. 2002; 9(5):1031-44. DOI: 10.1016/s1097-2765(02)00520-8. View

16.

Mandriota S, Turner K, Davies D, Murray P, Morgan N, Sowter H . HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron. Cancer Cell. 2002; 1(5):459-68. DOI: 10.1016/s1535-6108(02)00071-5. View

17.

Nikiforov M, Chandriani S, OConnell B, Petrenko O, Kotenko I, Beavis A . A functional screen for Myc-responsive genes reveals serine hydroxymethyltransferase, a major source of the one-carbon unit for cell metabolism. Mol Cell Biol. 2002; 22(16):5793-800. PMC: 133987. DOI: 10.1128/MCB.22.16.5793-5800.2002. View

18.

Koumenis C, Naczki C, Koritzinsky M, Rastani S, Diehl A, Sonenberg N . Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2alpha. Mol Cell Biol. 2002; 22(21):7405-16. PMC: 135664. DOI: 10.1128/MCB.22.21.7405-7416.2002. View

19.

Gomez-Roman N, Grandori C, Eisenman R, White R . Direct activation of RNA polymerase III transcription by c-Myc. Nature. 2003; 421(6920):290-4. DOI: 10.1038/nature01327. View

20.

OConnell B, Cheung A, Simkevich C, Tam W, Ren X, Mateyak M . A large scale genetic analysis of c-Myc-regulated gene expression patterns. J Biol Chem. 2003; 278(14):12563-73. DOI: 10.1074/jbc.M210462200. View