Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

The interplay between MYC and HIF in cancer

Nature Reviews Cancer volume 8, pages 51–56 (2008)Cite this article

Abstract

The interaction of MYC and hypoxia inducible factors (HIFs) under physiological, non-tumorigenic conditions provides insights into normal homeostatic cellular responses to low oxygen levels (hypoxia). Many tumours contain genetic alterations, such as MYC activation, that can collaborate with HIF to confer metabolic advantages to tumour cells, which tend to exist in a hypoxic microenvironment. This Perspective emphasizes the differences between the transcriptional network that operates under normal homeostatic conditions and the network in a tumorigenic milieu.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The HIF1, HIF2 and MYC protein–protein interaction transcriptional network.
Figure 2: Stoichiometric changes affecting MYC–HIF1 interactions in physiological versus oncogenic scenarios.
Figure 3: Molecular aspects of the Warburg effect and MYC–HIF1 interactions.

Similar content being viewed by others

References

  1. Shchors, K. & Evan, G. Tumor angiogenesis: cause or consequence of cancer? Cancer Res. 67, 7059–7061 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Adhikary, S. & Eilers, M. Transcriptional regulation and transformation by Myc proteins. Nature Rev. Mol. Cell Biol. 6, 635–645 (2005).

    Article  CAS  Google Scholar 

  3. Gordan, J. D. & Simon, M. C. Hypoxia-inducible factors: central regulators of the tumor phenotype. Curr. Opin. Genet. Dev. 17, 71–77 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Gordan, J. D., Thompson, C. B. & Simon, M. C. HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. Cancer Cell 12, 108–113 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Semenza, G. L. Targeting HIF-1 for cancer therapy. Nature Rev. Cancer 3, 721–732 (2003).

    Article  CAS  Google Scholar 

  6. Lawlor, E. R. et al. Reversible kinetic analysis of Myc targets in vivo provides novel insights into Myc-mediated tumorigenesis. Cancer Res. 66, 4591–4601 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Dang, C. V. et al. The c-Myc target gene network. Semin. Cancer Biol. 16, 253–264 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Liu, J. & Levens, D. Making myc. Curr. Top. Microbiol. Immunol. 302, 1–32 (2006).

    CAS  PubMed  Google Scholar 

  9. Chung, H. J. & Levens, D. c-myc expression: keep the noise down! Mol. Cells 20, 157–166 (2005).

    CAS  PubMed  Google Scholar 

  10. Grandori, C., Cowley, S. M., James, L. P. & Eisenman, R. N. The Myc/Max/Mad network and the transcriptional control of cell behavior. Annu. Rev. Cell Dev. Biol. 16, 653–699 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. Baudino, T. A. & Cleveland, J. L. The Max network gone mad. Mol. Cell Biol. 21, 691–702 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zeller, K. I., Jegga, A. G., Aronow, B. J., O'Donnell, K. A. & Dang, C. V. An integrated database of genes responsive to the Myc oncogenic transcription factor: identification of direct genomic targets. Genome Biol. 4, R69 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Zeller, K. I. et al. Global mapping of c-Myc binding sites and target gene networks in human B cells. Proc. Natl Acad. Sci. USA 103, 17834–17839 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Schreiber-Agus, N. et al. Drosophila Myc is oncogenic in mammalian cells and plays a role in the diminutive phenotype. Proc. Natl Acad. Sci. USA 94, 1235–1240 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gallant, P., Shiio, Y., Cheng, P. F., Parkhurst, S. M. & Eisenman, R. N. Myc and Max homologs in Drosophila. Science 274, 1523–1527 (1996).

    Article  CAS  PubMed  Google Scholar 

  16. Greasley, P. J., Bonnard, C. & Amati, B. Myc induces the nucleolin and BN51 genes: possible implications in ribosome biogenesis. Nucleic Acids Res. 28, 446–453 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Fernandez, P. C. et al. Genomic targets of the human c-Myc protein. Genes Dev. 17, 1115–1129 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Grewal, S. S., Li, L., Orian, A., Eisenman, R. N. & Edgar, B. A. Myc-dependent regulation of ribosomal RNA synthesis during Drosophila development. Nature Cell Biol. 7, 295–302 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Grandori, C. et al. c-Myc binds to human ribosomal DNA and stimulates transcription of rRNA genes by RNA polymerase I. Nature Cell Biol. 7, 311–318 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Gomez-Roman, N., Grandori, C., Eisenman, R. N. & White, R. J. Direct activation of RNA polymerase III transcription by c-Myc. Nature 421, 290–294 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Osthus, R. C. et al. Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J. Biol. Chem. 275, 21797–21800 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. Shim, H. et al. c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proc. Natl Acad. Sci. USA 94, 6658–6663 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kim, J. W. et al. Evaluation of myc E-box phylogenetic footprints in glycolytic genes by chromatin immunoprecipitation assays. Mol. Cell Biol. 24, 5923–5936 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Li, F. et al. Myc stimulates nuclearly encoded mitochondrial genes and mitochondrial biogenesis. Mol. Cell Biol. 25, 6225–6234 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhang, H. et al. HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell 11, 407–420 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Brahimi-Horn, M. C., Chiche, J. & Pouyssegur, J. Hypoxia signalling controls metabolic demand. Curr. Opin. Cell Biol. 19, 223–229 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Brunelle, J. K. et al. Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation. Cell Metab. 1, 409–414 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Guzy, R. D. et al. Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metab. 1, 401–408 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Kaelin, W. G. Jr. ROS: really involved in oxygen sensing. Cell Metab. 1, 357–358 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Lu, H. et al. Reversible inactivation of HIF-1 prolyl hydroxylases allows cell metabolism to control basal HIF-1. J. Biol. Chem. 280, 41928–41939 (2005).

    Article  CAS  PubMed  Google Scholar 

  31. Semenza, G. L. et al. Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J. Biol. Chem. 271, 32529–32537 (1996).

    Article  CAS  PubMed  Google Scholar 

  32. Semenza, G. L., Roth, P. H., Fang, H. M. & Wang, G. L. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J. Biol. Chem. 269, 23757–23763 (1994).

    CAS  PubMed  Google Scholar 

  33. Papandreou, I., Cairns, R. A., Fontana, L., Lim, A. L. & Denko, N. C. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 3, 187–197 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Kim, J. W., Tchernyshyov, I., Semenza, G. L. & Dang, C. V. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 3, 177–185 (2006).

    Article  PubMed  Google Scholar 

  35. Fukuda, R. et al. HIF-1 regulates cytochrome oxidase subunit composition to optimize efficiency of respiration in hypoxic cells. Cell 129, 111–122 (2007)

    Article  CAS  PubMed  Google Scholar 

  36. Goda, N. et al. Hypoxia-inducible factor 1α is essential for cell cycle arrest during hypoxia. Mol. Cell Biol. 23, 359–369 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Green, S. L., Freiberg, R. A. & Giaccia, A. J. p21(Cip1) and p27(Kip1) regulate cell cycle reentry after hypoxic stress but are not necessary for hypoxia-induced arrest. Mol. Cell Biol. 21, 1196–1206 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Gardner, L. B. et al. Hypoxia inhibits G1/S transition through regulation of p27 expression. J. Biol. Chem. 276, 7919–7926 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Koshiji, M. et al. HIF-1α induces cell cycle arrest by functionally counteracting Myc. EMBO J. 23, 1949–1956 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kleine-Kohlbrecher, D., Adhikary, S. & Eilers, M. Mechanisms of transcriptional repression by Myc. Curr. Top. Microbiol. Immunol. 302, 51–62 (2006).

    CAS  Google Scholar 

  41. Koshiji, M. et al. HIF-1α induces genetic instability by transcriptionally downregulating MutSα expression. Mol. Cell 17, 793–803 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. To, K. K., Sedelnikova, O. A., Samons, M., Bonner, W. M. & Huang, L. E. The phosphorylation status of PAS-B distinguishes HIF-1α from HIF-2α in NBS1 repression. EMBO J. 25, 4784–4794 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Vafa, O. et al. c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: a mechanism for oncogene-induced genetic instability. Mol. Cell 9, 1031–1044 (2002).

    Article  CAS  PubMed  Google Scholar 

  44. Karlsson, A. et al. Genomically complex lymphomas undergo sustained tumor regression upon MYC inactivation unless they acquire novel chromosomal translocations. Blood 101, 2797–2803 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Gardner, L. B., Li, F., Yang, X. & Dang, C. V. Anoxic fibroblasts activate a replication checkpoint that is bypassed by E1a. Mol. Cell Biol. 23, 9032–9045 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Corn, P. G. et al. Mxi1 is induced by hypoxia in a HIF-1-dependent manner and protects cells from c-Myc-induced apoptosis. Cancer Biol. Ther. 4, 1285–1294 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. O'Hagan, R. C. et al. Gene-target recognition among members of the myc superfamily and implications for oncogenesis. Nature Genet. 24, 113–119 (2000).

    Article  CAS  PubMed  Google Scholar 

  48. Gordan, J. D., Bertout, J. A., Hu, C. J., Diehl, J. A. & Simon, M. C. HIF-2α promotes hypoxic cell proliferation by enhancing c-Myc transcriptional activity. Cancer Cell 11, 335–347 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Tian, H., McKnight, S. L. & Russell, D. W. Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev. 11, 72–82 (1997).

    Article  CAS  PubMed  Google Scholar 

  50. Dang, C. V. c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol. Cell Biol. 19, 1–11 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Oster, S. K., Ho, C. S., Soucie, E. L. & Penn, L. Z. The myc oncogene: MarvelouslY Complex. Adv. Cancer Res. 84, 81–154 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. Smith, D. P., Bath, M. L., Metcalf, D., Harris, A. W. & Cory, S. MYC levels govern hematopoietic tumor type and latency in transgenic mice. Blood 108, 653–661 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Arvanitis, C. & Felsher, D. W. Conditional transgenic models define how MYC initiates and maintains tumorigenesis. Semin. Cancer Biol. 16, 313–317 (2006).

    Article  CAS  PubMed  Google Scholar 

  54. Alarcon, R. M., Rupnow, B. A., Graeber, T. G., Knox, S. J. & Giaccia, A. J. Modulation of c-Myc activity and apoptosis in vivo. Cancer Res. 56, 4315–4319 (1996).

    CAS  PubMed  Google Scholar 

  55. Rupnow, B. A., Alarcon, R. M., Giaccia, A. J. & Knox, S. J. p53 mediates apoptosis induced by c-Myc activation in hypoxic or gamma irradiated fibroblasts. Cell Death Differ. 5, 141–147 (1998).

    Article  CAS  PubMed  Google Scholar 

  56. Cleveland, J. L. & Sherr, C. J. Antagonism of Myc functions by Arf. Cancer Cell 6, 309–311 (2004).

    Article  CAS  PubMed  Google Scholar 

  57. Gao, P. et al. HIF-dependent anti-tumorigenic effect of anti-oxidants in vivo. Cancer Cell 12, 230–238 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Blouw, B. et al. The hypoxic response of tumors is dependent on their microenvironment. Cancer Cell 4, 133–146 (2003).

    Article  CAS  PubMed  Google Scholar 

  59. Ryan, H. E. et al. Hypoxia-inducible factor-1α is a positive factor in solid tumor growth. Cancer Res. 60, 4010–4015 (2000).

    CAS  PubMed  Google Scholar 

  60. Kim, J. W., Gao, P., Liu, Y. C., Semenza, G. L. & Dang, C. V. HIF-1 and dysregulated c-Myc cooperatively induces VEGF and metabolic switches, HK2 and PDK1. Mol. Cell Biol. (2007).

  61. Warburg, O. The Metabolism of Tumours (Constable & Co., London, 1930).

    Google Scholar 

  62. Warburg, O. On the origin of cancer cells. Science 123, 309–314 (1956).

    Article  CAS  PubMed  Google Scholar 

  63. Helmlinger, G., Yuan, F., Dellian, M. & Jain, R. K. Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nature Med. 3, 177–182 (1997).

    Article  CAS  PubMed  Google Scholar 

  64. Plas, D. R. & Thompson, C. B. Akt-dependent transformation: there is more to growth than just surviving. Oncogene 24, 7435–7442 (2005).

    Article  CAS  PubMed  Google Scholar 

  65. Kim, J. W. & Dang, C. V. Cancer's molecular sweet tooth and the Warburg effect. Cancer Res. 66, 8927–8930 (2006).

    Article  CAS  PubMed  Google Scholar 

  66. Dewhirst, M. W. Intermittent hypoxia furthers the rationale for hypoxia-inducible factor-1 targeting. Cancer Res. 67, 854–855 (2007).

    Article  CAS  PubMed  Google Scholar 

  67. Gazit, Y. et al. Fractal characteristics of tumor vascular architecture during tumor growth and regression. Microcirculation 4, 395–402 (1997).

    Article  CAS  PubMed  Google Scholar 

  68. Gatenby, R. A. & Gillies, R. J. Why do cancers have high aerobic glycolysis? Nature Rev. Cancer 4, 891–899 (2004).

    Article  CAS  Google Scholar 

  69. Tatsumi, M., Cohade, C., Nakamoto, Y., Fishman, E. K. & Wahl, R. L. Direct comparison of FDG PET and CT findings in patients with lymphoma: initial experience. Radiology 237, 1038–1045 (2005).

    Article  PubMed  Google Scholar 

  70. Kim, J. W. & Dang, C. V. Multifaceted roles of glycolytic enzymes. Trends Biochem. Sci. 30, 142–150 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. Bonnet, S. et al. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11, 37–51 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. Fantin, V. R., St-Pierre, J. & Leder, P. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9, 425–434 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. O'Donnell, K. A. et al. Activation of transferrin receptor 1 by c-Myc enhances cellular proliferation and tumorigenesis. Mol. Cell Biol. 26, 2373–2386 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Tacchini, L., Bianchi, L., Bernelli-Zazzera, A. & Cairo, G. Transferrin receptor induction by hypoxia. HIF-1-mediated transcriptional activation and cell-specific post-transcriptional regulation. J. Biol. Chem. 274, 24142–24146 (1999).

    Article  CAS  PubMed  Google Scholar 

  75. Pandey, M. K. et al. Gambogic acid, a novel ligand for transferrin receptor, potentiates TNF-induced apoptosis through modulation of the nuclear factor-κB signaling pathway. Blood 110, 3517–3525 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Kasibhatla, S. et al. A role for transferrin receptor in triggering apoptosis when targeted with gambogic acid. Proc. Natl Acad. Sci. USA 102, 12095–12100 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Louro, I. D. et al. Comparative gene expression profile analysis of GLI and c-MYC in an epithelial model of malignant transformation. Cancer Res. 62, 5867–5873 (2002).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. the Division of Hematology, Department of Medicine, Chi V. Dang is also at the Department of Cell Biology, the Department of Oncology and the Department of Pathology, and Jason Yustein is at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and the Department of Pediatrics, Chi V. Dang and Ping Gao are at, and Jung-whan Kim was at, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.,

    Chi V. Dang, Jung-whan Kim, Ping Gao & Jason Yustein

  2. Jung-whan Kim is now at the Department of Anatomy, University of California, San Francisco, Health Science West 1301, 513 Parnassus Avenue, San Francisco, California 94143, USA.,

    Jung-whan Kim

Authors
  1. Chi V. Dang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jung-whan Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ping Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jason Yustein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chi V. Dang.

Related links

Related links

FURTHER INFORMATION

MYC target genes website

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dang, C., Kim, Jw., Gao, P. et al. The interplay between MYC and HIF in cancer. Nat Rev Cancer 8, 51–56 (2008). https://doi.org/10.1038/nrc2274

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc2274

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing