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.

  • Review Article
  • Published:

HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression

Key Points

  • Hypoxia-inducible factor 1α (HIF1α) and HIF2α are broadly expressed in many human cancers, and expression of these proteins frequently correlate with poor patient prognosis.

  • Although HIF1α and HIF2α share some redundant functions, they also exhibit unique and even opposing activities in cell growth, metabolism, angiogenesis, nitric oxide homeostasis and other processes that affect tumour growth.

  • A careful genetic dissection of Hif1a versus Epas1 (which encodes HIF2α) in autochthonous mouse models of cancer is underway, but is only in its infancy. Given that recent results have revealed unanticipated roles for the HIFα subunits in these assays, more work is clearly needed.

  • The HIFs affect many key aspects of tumour initiation, progression, invasion, inflammatory cell recruitment and metastasis; therefore, they represent attractive targets for novel targeted therapies.

  • Surprisingly, HIF1α can function as a tumour suppressor in renal cell carcinoma, whereas HIF2α functions as a tumour suppressor in lung adenocarcinoma. Because HIF inhibitors are being developed for therapeutic benefit, possible tumour-suppressive roles for the HIFs in a minority of human cancers should be carefully assessed.

Abstract

Hypoxia-inducible factors (HIFs) are broadly expressed in human cancers, and HIF1α and HIF2α were previously suspected to promote tumour progression through largely overlapping functions. However, this relatively simple model has now been challenged in light of recent data from various approaches that reveal unique and sometimes opposing activities of these HIFα isoforms in both normal physiology and disease. These effects are mediated in part through the regulation of unique target genes, as well as through direct and indirect interactions with important oncoproteins and tumour suppressors, including MYC and p53. As HIF inhibitors are currently undergoing clinical evaluation as cancer therapeutics, a more thorough understanding of the unique roles performed by HIF1α and HIF2α in human neoplasia is warranted.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: HIF1α and HIF2α exhibit antagonistic functions in NO production.
Figure 2: HIF1α and HIF2α are post-translationally modified and differentially regulated by multiple mechanisms.
Figure 3: Differential regulation of HIF1α and HIF2α by SIRT1.
Figure 4: Distinct effects of HIF1α and HIF2α on MYC complex formation and promoter occupancy.

Similar content being viewed by others

References

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

    Article  CAS  Google Scholar 

  2. Bertout, J. A., Patel, S. A. & Simon, M. C. The impact of O2 availability on human cancer. Nature Rev. Cancer 8, 967–975 (2008).

    Article  CAS  Google Scholar 

  3. Rankin, E. B. & Giaccia, A. J. The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ. 15, 678–685 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Kaelin, W. G. Jr & Ratcliffe, P. J. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol. Cell 30, 393–402 (2008).

    Article  CAS  PubMed  Google Scholar 

  5. Majmundar, A. J., Wong, W. J. & Simon, M. C. Hypoxia-inducible factors and the response to hypoxic stress. Mol. Cell 40, 294–309 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Pouyssegur, J., Dayan, F. & Mazure, N. M. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 441, 437–443 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Wang, G. L., Jiang, B.-H., Rue, E. A. & Semenza, G. L. Hypoxia-inducible factor 1 is a basic-helix–loop–helix–PAS heterodimer regulated by cellular O2 tension. Proc. Natl Acad. Sci. USA 92, 5510–5514 (1995). The initial characterization and cloning of the HIF1A and ARNT (which encodes HIF1β) cDNAs, showing the O 2 -labile nature of the HIF1α subunit as a mechanism that regulates the expression of hypoxia-induced target genes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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). The initial characterization of HIF2α (followed rapidly by references 9–11), demonstrating a similar protein structure to HIF1α, as well as a restricted spatial expression pattern and distinct transcriptional activity using a Tek reporter gene.

    Article  CAS  PubMed  Google Scholar 

  9. Flamme, I. et al. HRF, a putative basic helix-loop-helix-PAS-domain transcription factor is closely related to hypoxia-inducible factor-1α and developmentally expressed in blood vessels. Mech. Dev. 63, 51–60 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Ema, M. et al. A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1α regulates the VEGF expression and is potentially involved in lung and vascular development. Proc. Natl Acad. Sci. USA 94, 4273–4278 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hogenesch, J. B. et al. Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway. J. Biol. Chem. 272, 8581–8593 (1997).

    Article  CAS  PubMed  Google Scholar 

  12. Wiesener, M. S. et al. Widespread hypoxia-inducible expression of HIF-2α in distinct cell populations of different organs. FASEB J. 17, 271–273 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Makino, Y., Kanopka, A., Wilson, W. J., Tanaka, H. & Poellinger, L. Inhibitory PAS domain protein (IPAS) is a hypoxia-inducible splicing variant of the hypoxia-inducible factor-3α locus. J. Biol. Chem. 277, 32405–32408 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Heikkila, M., Pasanen, A., Kivirikko, K. I. & Myllyharju, J. Roles of the human hypoxia-inducible factor (HIF)-3α variants in the hypoxia response. Cell. Mol. Life Sci. 68, 3885–3901 (2011).

    Article  CAS  PubMed  Google Scholar 

  15. Tanaka, T., Wiesener, M., Bernhardt, W., Eckardt, K. U. & Warnecke, C. The human HIF (hypoxia-inducible factor)-3α gene is a HIF-1 target gene and may modulate hypoxic gene induction. Biochem. J. 424, 143–151 (2009).

    Article  CAS  PubMed  Google Scholar 

  16. Maynard, M. A. et al. Multiple splice variants of the human HIF-3α locus are targets of the von Hippel-Lindau E3 ubiquitin ligase complex. J. Biol. Chem. 278, 11032–11040 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Maynard, M. A. et al. Dominant-negative HIF-3α4 suppresses VHL-null renal cell carcinoma progression. Cell Cycle 6, 2810–2816 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Hirose, K. et al. cDNA cloning and tissue-specific expression of a novel basic helix-loop-helix/PAS factor (Arnt2) with close sequence similarity to the Aryl hydrocarbon receptor nuclear translocator (Arnt). Mol. Cell. Biol. 16, 1706–1713 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Michaud, J. L., DeRossi, C., May, N. R., Holdener, B. C. & Fan, C. ARNT2 acts as the dimerization partner of SIM1 for the development of the hypothalamus. Mech. Dev. 90, 253–261 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Keith, B., Adelman, D. M. & Simon, M. C. Targeted mutation of the murine arylhydrocarbon receptor nuclear translocator 2 (Arnt2) gene reveals partial redundancy with Arnt. Proc. Natl Acad. Sci. USA 98, 6692–6697 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Qin, X. Y. et al. siRNA-mediated knockdown of aryl hydrocarbon receptor nuclear translocator 2 affects hypoxia-inducible factor-1 regulatory signaling and metabolism in human breast cancer cells. FEBS Lett. 585, 3310–3315 (2011).

    Article  CAS  PubMed  Google Scholar 

  22. Kaelin, W. G. Jr. The von Hippel-Lindau tumour suppressor protein: O2 sensing and cancer. Nature Rev. Cancer 8, 865–873 (2008).

    Article  CAS  Google Scholar 

  23. Maranchie, J. K. et al. The contribution of VHL substrate binding and HIF1-α to the phenotype of VHL loss in renal cell carcinoma. Cancer Cell 1, 247–255 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Kondo, K., Kim, W. Y., Lechpammer, M. & Kaelin, W. G. Jr. Inhibition of HIF2α is sufficient to suppress pVHL-defective tumor growth. PLoS Biol. 1, e83 (2003). References 23 and 24 describe the surprising findings that the expression of HIF2α specifically promoted the growth of RCC xenograft tumours, whereas the expression of HIF1α suppressed their growth.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Acker, T. et al. Genetic evidence for a tumor suppressor role of HIF-2α. Cancer Cell 8, 131–141 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Mazumdar, J. et al. HIF-2α deletion promotes Kras-driven lung tumor development. Proc. Natl Acad. Sci. USA 107, 14182–14187 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hu, C.-J., Wang, L.-Y., Chodosh, L. A., Keith, B. & Simon, M. C. Differential roles of hypoxia-inducible factor 1α (HIF-1α) and HIF-2α in hypoxic gene regulation. Mol. Biol. Cell 23, 9361–9374 (2003).

    Article  CAS  Google Scholar 

  28. Raval, R. R. et al. Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma. Mol. Cell. Biol. 25, 5675–5686 (2005). References 27 and 28 demonstrate that HIF1α and HIF2α regulate overlapping, but not identical, sets of target genes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hu, C. J., Sataur, A., Wang, L., Chen, H. & Simon, M. C. The N-terminal transactivation domain confers target gene specificity of hypoxia-inducible factors HIF-1α and HIF-2α. Mol. Biol. Cell 18, 4528–4542 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lau, K. W., Tian, Y. M., Raval, R. R., Ratcliffe, P. J. & Pugh, C. W. Target gene selectivity of hypoxia-inducible factor-α in renal cancer cells is conveyed by post-DNA-binding mechanisms. Br. J. Cancer 96, 1284–1292 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Xia, X. et al. Integrative analysis of HIF binding and transactivation reveals its role in maintaining histone methylation homeostasis. Proc. Natl Acad. Sci. USA 106, 4260–4265 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Xia, X. & Kung, A. L. Preferential binding of HIF-1 to transcriptionally active loci determines cell-type specific response to hypoxia. Genome Biol. 10, R113 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Mole, D. R. et al. Genome-wide association of hypoxia-inducible factor (HIF)-1α and HIF-2α DNA binding with expression profiling of hypoxia-inducible transcripts. J. Biol. Chem. 284, 16767–16775 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Krieg, A. J. et al. Regulation of the histone demethylase JMJD1A by hypoxia-inducible factor 1α enhances hypoxic gene expression and tumor growth. Mol. Cell. Biol. 30, 344–353 (2010).

    Article  CAS  PubMed  Google Scholar 

  35. Schodel, J. et al. High-resolution genome-wide mapping of HIF-binding sites by ChIP-seq. Blood 117, e207–e217 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Iyer, N. V. et al. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1α. Genes Dev. 12, 149–162 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ryan, H. E., Lo, J. & Johnson, R. S. HIF-1α is required for solid tumor formation and embryonic vascularization. EMBO J. 17, 3005–3015 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Tian, H., Hammer, R. E., Matsumoto, A. M., Russell, D. W. & McKnight, S. L. The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. Genes Dev. 12, 3320–3324 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Compernolle, V. et al. Loss of HIF-2α and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice. Nature Med. 8, 702–710 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Peng, J., Zhang, L., Drysdale, L. & Fong, G. H. The transcription factor EPAS-1/hypoxia-inducible factor 2α plays an important role in vascular remodeling. Proc. Natl Acad. Sci. USA 97, 8386–8391 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Scortegagna, M. et al. Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1−/− mice. Nature Genet. 35, 331–340 (2003).

    Article  CAS  PubMed  Google Scholar 

  42. Gruber, M. et al. Acute postnatal ablation of Hif-2α results in anemia. Proc. Natl Acad. Sci. USA 104, 2301–2306 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Liao, D., Corle, C., Seagroves, T. N. & Johnson, R. S. Hypoxia-inducible factor-1α is a key regulator of metastasis in a transgenic model of cancer initiation and progression. Cancer Res. 67, 563–572 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Krop, I. et al. HIN-1, an inhibitor of cell growth, invasion, and AKT activation. Cancer Res. 65, 9659–9669 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Kim, W. Y. et al. HIF2α cooperates with RAS to promote lung tumorigenesis in mice. J. Clin. Invest. 119, 2160–2170 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Rankin, E. B. et al. Hypoxia-inducible factor-2 regulates vascular tumorigenesis in mice. Oncogene 27, 5354–5358 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Fang, H. Y. et al. Hypoxia-inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia. Blood 114, 844–859 (2009).

    Article  CAS  PubMed  Google Scholar 

  48. Doedens, A. L. et al. Macrophage expression of hypoxia-inducible factor-1α suppresses T-cell function and promotes tumor progression. Cancer Res. 70, 7465–7475 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Takeda, N. et al. Differential activation and antagonistic function of HIF-α isoforms in macrophages are essential for NO homeostasis. Genes Dev. 24, 491–501 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Imtiyaz, H. Z. et al. Hypoxia-inducible factor 2α regulates macrophage function in mouse models of acute and tumor inflammation. J. Clin. Invest. 120, 2699–2714 (2010). References 48–50 revealed that the expression of HIF1α and HIF2α in macrophages regulates tumour growth by altering innate and/or adaptive immune responses, primarily by regulating independent sets of target genes, some with opposing functions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Tang, N. et al. Loss of HIF-1α in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis. Cancer Cell 6, 485–495 (2004).

    Article  CAS  PubMed  Google Scholar 

  52. Yamashita, T. et al. Hypoxia-inducible transcription factor-2α in endothelial cells regulates tumor neovascularization through activation of ephrin A1. J. Biol. Chem. 283, 18926–18936 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Skuli, N. et al. Endothelial deletion of hypoxia-inducible factor-2α (HIF-2α) alters vascular function and tumor angiogenesis. Blood 114, 469–477 (2009). References 51–53 demonstrated that disrupting either HIF1α or HIF2α expression in vascular endothelial cells inhibited tumour angiogenesis, despite each HIFα subunit regulating distinct target genes in endothelial cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Belaiba, R. S. et al. Hypoxia up-regulates hypoxia-inducible factor-1αtranscription by involving phosphatidylinositol 3-kinase and nuclear factor κB in pulmonary artery smooth muscle cells. Mol. Biol. Cell 18, 4691–4697 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Frede, S., Stockmann, C., Freitag, P. & Fandrey, J. Bacterial lipopolysaccharide induces HIF-1 activation in human monocytes via p44/42 MAPK and NF-κB. Biochem. J. 396, 517–527 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Nizet, V. & Johnson, R. S. Interdependence of hypoxic and innate immune responses. Nature Rev. Immunol. 9, 609–617 (2009).

    Article  CAS  Google Scholar 

  57. Rius, J. et al. NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α. Nature 453, 807–811 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kenneth, N. S., Mudie, S., van Uden, P. & Rocha, S. SWI/SNF regulates the cellular response to hypoxia. J. Biol. Chem. 284, 4123–4131 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Toschi, A., Lee, E., Gadir, N., Ohh, M. & Foster, D. A. Differential dependence of hypoxia-inducible factors 1α and 2α on mTORC1 and mTORC2. J. Biol. Chem. 283, 34495–34499 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Uchida, T. et al. Prolonged hypoxia differentially regulates hypoxia-inducible factor (HIF)-1α and HIF-2α expression in lung epithelial cells: implication of natural antisense HIF-1α. J. Biol. Chem. 279, 14871–14878 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Sanchez, M., Galy, B., Muckenthaler, M. U. & Hentze, M. W. Iron-regulatory proteins limit hypoxia-inducible factor-2α expression in iron deficiency. Nature Struct. Mol. Biol. 14, 420–426 (2007).

    Article  CAS  Google Scholar 

  62. Zimmer, M. et al. Small-molecule inhibitors of HIF-2a translation link its 5′UTR iron-responsive element to oxygen sensing. Mol. Cell 32, 838–848 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lee, F. S. & Percy, M. J. The HIF pathway and erythrocytosis. Annu. Rev. Pathol. 6, 165–192 (2011).

    Article  CAS  PubMed  Google Scholar 

  64. Mastrogiannaki, M. et al. HIF-2α, but not HIF-1α, promotes iron absorption in mice. J. Clin. Invest. 119, 1159–1166 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Rankin, E. B. et al. Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo. J. Clin. Invest. 117, 1068–1077 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Morita, M. et al. HLF/HIF-2α is a key factor in retinopathy of prematurity in association with erythropoietin. EMBO J. 22, 1134–1146 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Nilsson, H. et al. HIF-2α expression in human fetal paraganglia and neuroblastoma: relation to sympathetic differentiation, glucose deficiency, and hypoxia. Exp. Cell Res. 303, 447–456 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. Holmquist-Mengelbier, L. et al. Recruitment of HIF-1α and HIF-2α to common target genes is differentially regulated in neuroblastoma: HIF-2α promotes an aggressive phenotype. Cancer Cell 10, 413–423 (2006).

    Article  CAS  PubMed  Google Scholar 

  69. Li, Z. et al. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell 15, 501–513 (2009). References 67–69 demonstrated that HIF2α is preferentially stabilized in neuroblastomas and glioblastomas and is associated with an aggressive tumour phenotype.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Koh, M. Y., Darnay, B. G. & Powis, G. Hypoxia-associated factor, a novel E3-ubiquitin ligase, binds and ubiquitinates hypoxia-inducible factor 1α, leading to its oxygen-independent degradation. Mol. Cell. Biol. 28, 7081–7095 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Koh, M. Y., Lemos, R. Jr, Liu, X. & Powis, G. The hypoxia-associated factor switches cells from HIF-1α- to HIF-2α-dependent signaling promoting stem cell characteristics, aggressive tumor growth and invasion. Cancer Res. 71, 4015–4027 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Luo, W. et al. Hsp70 and CHIP selectively mediate ubiquitination and degradation of hypoxia-inducible factor (HIF)-1α but Not HIF-2α. J. Biol. Chem. 285, 3651–3663 (2010).

    Article  CAS  PubMed  Google Scholar 

  73. Jokilehto, T. & Jaakkola, P. M. The role of HIF prolyl hydroxylases in tumour growth. J. Cell. Mol. Med. 14, 758–770 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Chan, D. A. & Giaccia, A. J. PHD2 in tumour angiogenesis. Br. J. Cancer 103, 1–5 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Cockman, M. E., Webb, J. D. & Ratcliffe, P. J. FIH-dependent asparaginyl hydroxylation of ankyrin repeat domain-containing proteins. Ann. NY Acad. Sci. 1177, 9–18 (2009).

    Article  CAS  PubMed  Google Scholar 

  76. Appelhoff, R. J. et al. Differential function of the prolyl hydroxylases, PHD1, PHD2 and PHD3 in the regulation of hypoxia-inducible factor. J. Biol. Chem. 279, 38458–38465 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Bracken, C. P. et al. Cell-specific regulation of hypoxia-inducible factor (HIF)-1α and HIF-2α stabilization and transactivation in a graded oxygen environment. J. Biol. Chem. 281, 22575–22585 (2006).

    Article  CAS  PubMed  Google Scholar 

  78. Zhang, N. et al. The asparaginyl hydroxylase factor inhibiting HIF-1α is an essential regulator of metabolism. Cell Metab. 11, 364–378 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Richard, D. E., Berra, E., Gothie, E., Roux., D. & Pouyssegur, J. p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1α (HIF-1α) and enhance the transcriptional activity of HIF-1. J. Biol. Chem. 274, 32631–32637 (1999).

    Article  CAS  PubMed  Google Scholar 

  80. Conrad, P. W., Freeman, T. L., Beitner-Johnson, D. & Millhorn, D. E. EPAS1 trans-activation during hypoxia requires p42/p44 MAPK. J. Biol. Chem. 274, 33709–33713 (1999).

    Article  CAS  PubMed  Google Scholar 

  81. 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 

  82. Mylonis, I. et al. Identification of MAPK phosphorylation sites and their role in the localization and activity of hypoxia-inducible factor-1α. J. Biol. Chem. 281, 33095–33106 (2006).

    Article  CAS  PubMed  Google Scholar 

  83. Kalousi, A. et al. Casein kinase 1 regulates human hypoxia-inducible factor HIF-1. J. Cell Sci. 123, 2976–2986 (2010).

    Article  CAS  PubMed  Google Scholar 

  84. Cam, H., Easton, J. B., High, A. & Houghton, P. J. mTORC1 signaling under hypoxic conditions is controlled by ATM-dependent phosphorylation of HIF-1α. Mol. Cell 40, 509–520 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Finkel, T., Deng, C. X. & Mostoslavsky, R. Recent progress in the biology and physiology of sirtuins. Nature 460, 587–591 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Dioum, E. M. et al. Regulation of hypoxia-inducible factor 2α signaling by the stress-responsive deacetylase sirtuin 1. Science 324, 1289–1293 (2009).

    Article  CAS  PubMed  Google Scholar 

  87. Lim, J. H. et al. Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1α. Mol. Cell 38, 864–878 (2010).

    Article  CAS  PubMed  Google Scholar 

  88. Chen, R., Dioum, E. M., Hogg, R. T., Gerard, R. D. & Garcia, J. A. Hypoxia increases sirtuin 1 expression in a hypoxia-inducible factor-dependent manner. J. Biol. Chem. 286, 13869–13878 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Sayed, D. & Abdellatif, M. AKT-ing via microRNA. Cell Cycle 9, 3213–3217 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Zhong, L. et al. The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1α. Cell 140, 280–293 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Bell, E. L. & Guarente, L. The SirT3 divining rod points to oxidative stress. Mol. Cell 42, 561–568 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. 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 

  93. Mansfield, K. D. et al. Cytochrome C is required for cellular oxygen sensing and hypoxic HIF activation. Cell Metab. 1, 393–399 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. 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 

  95. Bell, E. L., Emerling, B. M., Ricoult, S. J. & Guarente, L. SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production. Oncogene 30, 2986–2996 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Finley, L. W. et al. SIRT3 opposes reprogramming of cancer cell metabolism through HIF1α destabilization. Cancer Cell 19, 416–428 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Jeong, J. W. et al. Regulation and destabilization of HIF-1α by ARD1-mediated acetylation. Cell 111, 709–720 (2002).

    Article  CAS  PubMed  Google Scholar 

  98. Yoo, Y. G., Kong, G. & Lee, M. O. Metastasis-associated protein 1 enhances stability of hypoxia-inducible factor-1α protein by recruiting histone deacetylase 1. EMBO J. 25, 1231–1241 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Bilton, R. et al. Arrest-defective-1 protein, an acetyltransferase, does not alter stability of hypoxia-inducible factor (HIF)-1α and is not induced by hypoxia or HIF. J. Biol. Chem. 280, 31132–31140 (2005).

    Article  CAS  PubMed  Google Scholar 

  100. Cheng, J., Kang, X., Zhang, S. & Yeh, E. T. SUMO-specific protease 1 is essential for stabilization of HIF1α during hypoxia. Cell 131, 584–595 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. van Hagen, M., Overmeer, R. M., Abolvardi, S. S. & Vertegaal, A. C. RNF4 and VHL regulate the proteasomal degradation of SUMO-conjugated Hypoxia-Inducible Factor-2α. Nucleic Acids Res. 38, 1922–1931 (2010).

    Article  CAS  PubMed  Google Scholar 

  102. Bae, S. H. et al. Sumoylation increases HIF-1α stability and its transcriptional activity. Biochem. Biophys. Res. Commun. 324, 394–400 (2004).

    Article  CAS  PubMed  Google Scholar 

  103. Carbia-Nagashima, A. et al. RSUME, a small RWD-containing protein, enhances SUMO conjugation and stabilizes HIF-1α during hypoxia. Cell 131, 309–323 (2007).

    Article  CAS  PubMed  Google Scholar 

  104. Huang, C. et al. SENP3 is responsible for HIF-1 transactivation under mild oxidative stress via p300 de-SUMOylation. EMBO J. 28, 2748–2762 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Li, F. et al. Regulation of HIF-1α stability through S-nitrosylation. Mol. Cell 26, 63–74 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Ryu, J. H. et al. Hypoxia-inducible factor α subunit stabilization by NEDD8 conjugation is reactive oxygen species-dependent. J. Biol. Chem. 286, 6963–6970 (2011).

    Article  CAS  PubMed  Google Scholar 

  107. 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 

  108. Dang, C. V., Kim, J. W., Gao, P. & Yustein, J. The interplay between MYC and HIF in cancer. Nature Rev. Cancer 8, 51–56 (2008).

    Article  CAS  Google Scholar 

  109. 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 

  110. 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). Reference 107 demonstrated that HIF1α could inhibit MYC activity through a transcription-independent mechanism, whereas reference 110 showed that HIF2α promotes MYC activity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. 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 

  112. 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 

  113. Gordan, J. D. et al. HIF-α effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma. Cancer Cell 14, 435–446 (2008). This paper showed that MYC activation was evident in human RCCs that expressed HIF2α, but not in RCCs that constitutively expressed both HIF1α and HIF2α. This revealed that RCCs could be stratified with respect to oncogenic signalling pathways based on HIFα expression patterns.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Kim, J. W., Gao, P., Liu, Y. C., Semenza, G. L. & Dang, C. V. Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1. Mol. Cell. Biol. 27, 7381–7393 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Qing, G. et al. Combinatorial regulation of neuroblastoma tumor progression by N-Myc and hypoxia inducible factor HIF-1α. Cancer Res. 70, 10351–10361 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Kaelin, W. G. Jr. Kidney cancer: now available in a new flavor. Cancer Cell 14, 423–424 (2008).

    Article  CAS  PubMed  Google Scholar 

  117. Vousden, K. H. & Prives, C. Blinded by the light: the growing complexity of p53. Cell 137, 413–431 (2009).

    Article  CAS  PubMed  Google Scholar 

  118. Lavin, M. F. & Gueven, N. The complexity of p53 stabilization and activation. Cell Death Differ. 13, 941–950 (2006).

    Article  CAS  PubMed  Google Scholar 

  119. Pan, Y., Oprysko, P. R., Asham, A. M., Koch, C. J. & Simon, M. C. p53 cannot be induced by hypoxia alone but responds to the hypoxic microenvironment. Oncogene 23, 4975–4983 (2004).

    Article  CAS  PubMed  Google Scholar 

  120. An, W. G. et al. Stabilization of wild-type p53 by hypoxia-inducible factor 1α. Nature 392, 405–408 (1998). The first indication that p53 and HIF1α interact in a complex, leading to subsequent papers (references 121–126) that revealed a complex set of interactions between p53 and HIFα proteins.

    Article  CAS  PubMed  Google Scholar 

  121. Sanchez-Puig, N., Veprintsev, D. B. & Fersht, A. R. Binding of natively unfolded HIF-1α ODD domain to p53. Mol. Cell 17, 11–21 (2005).

    Article  CAS  PubMed  Google Scholar 

  122. Chen, D., Li, M., Luo, J. & Gu, W. Direct interactions between HIF-1α and Mdm2 modulate p53 function. J. Biol. Chem. 278, 13595–13598 (2003).

    Article  CAS  PubMed  Google Scholar 

  123. Moeller, B. J. et al. Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer Cell 8, 99–110 (2005).

    Article  CAS  PubMed  Google Scholar 

  124. Ravi, R. et al. Regulation of tumor angiogenesis by p53-induced degradation of hypoxia- inducible factor 1α. Genes Dev. 14, 34–44 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Bertout, J. A. et al. HIF2α inhibition promotes p53 pathway activity, tumor cell death, and radiation responses. Proc. Natl Acad. Sci. USA 106, 14391–14396 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Roberts, A. M. et al. Suppression of hypoxia-inducible factor 2α restores p53 activity via Hdm2 and reverses chemoresistance of renal carcinoma cells. Cancer Res. 69, 9056–9064 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Sengupta, S., Peterson, T. R. & Sabatini, D. M. Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Mol. Cell 40, 310–322 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Menon, S. & Manning, B. D. Common corruption of the mTOR signaling network in human tumors. Oncogene 27 (Suppl. 2), S43–S51 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Liu, L. et al. Hypoxia-induced energy stress regulates mRNA translation and cell growth. Mol. Cell 21, 521–531 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Brugarolas, J. et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev. 18, 2893–2904 (2004). The first report of HIF1α-dependent REDD1 expression leading to inhibition of mTOR activity under hypoxic conditions, followed by additional papers (references 129, 131–134) characterizing hypoxic control of mTOR-mediated cell growth.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. DeYoung, M. P., Horak, P., Sofer, A., Sgroi, D. & Ellisen, L. W. Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes Dev. 22, 239–251 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Li, Y. et al. Bnip3 mediates the hypoxia-induced inhibition on mammalian target of rapamycin by interacting with Rheb. J. Biol. Chem. 282, 35803–35813 (2007).

    Article  CAS  PubMed  Google Scholar 

  133. Gan, B., Melkoumian, Z. K., Wu, X., Guan, K. L. & Guan, J. L. Identification of FIP200 interaction with the TSC1-TSC2 complex and its role in regulation of cell size control. J. Cell Biol. 170, 379–389 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Chano, T. et al. Neuromuscular abundance of RB1CC1 contributes to the non-proliferating enlarged cell phenotype through both RB1 maintenance and TSC1 degradation. Int. J. Mol. Med. 18, 425–432 (2006).

    CAS  PubMed  Google Scholar 

  135. Morris, M. R. et al. Mutation analysis of hypoxia-inducible factors HIF1A and HIF2A in renal cell carcinoma. Anticancer Res. 29, 4337–4343 (2009).

    CAS  PubMed  Google Scholar 

  136. Dalgliesh, G. L. et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463, 360–363 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Beroukhim, R. et al. Patterns of gene expression and copy-number alterations in von-hippel lindau disease-associated and sporadic clear cell carcinoma of the kidney. Cancer Res. 69, 4674–4681 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Purdue, M. P. et al. Genome-wide association study of renal cell carcinoma identifies two susceptibility loci on 2p21 and 11q13.3. Nature Genet. 43, 60–65 (2010).

    Article  PubMed  CAS  Google Scholar 

  139. Semenza, G. L. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29, 625–634 (2010).

    Article  CAS  PubMed  Google Scholar 

  140. Rapisarda, A. et al. Identification of small molecule inhibitors of hypoxia-inducible factor 1 transcriptional activation pathway. Cancer Res. 62, 4316–4324 (2002).

    CAS  PubMed  Google Scholar 

  141. Lee, K. et al. Acriflavine inhibits HIF-1 dimerization, tumor growth, and vascularization. Proc. Natl Acad. Sci. USA 106, 17910–17915 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Majumder, P. K. et al. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nature Med. 10, 594–601 (2004).

    Article  CAS  PubMed  Google Scholar 

  143. Thomas, G. V. et al. Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nature Med. 12, 122–127 (2006).

    Article  CAS  PubMed  Google Scholar 

  144. Kong, X. et al. Histone deacetylase inhibitors induce VHL and ubiquitin-independent proteasomal degradation of hypoxia-inducible factor 1α. Mol. Cell. Biol. 26, 2019–2028 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Qian, D. Z. et al. Class II histone deacetylases are associated with VHL-independent regulation of hypoxia-inducible factor 1α. Cancer Res. 66, 8814–8821 (2006).

    Article  CAS  PubMed  Google Scholar 

  146. Isaacs, J. S. et al. Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1α-degradative pathway. J. Biol. Chem. 277, 29936–29944 (2002).

    Article  CAS  PubMed  Google Scholar 

  147. Mabjeesh, N. J. et al. Geldanamycin induces degradation of hypoxia-inducible factor 1α protein via the proteosome pathway in prostate cancer cells. Cancer Res. 62, 2478–2482 (2002).

    CAS  PubMed  Google Scholar 

  148. Moeller, B. J., Cao, Y., Li, C. Y. & Dewhirst, M. W. Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell 5, 429–441 (2004).

    Article  CAS  PubMed  Google Scholar 

  149. Lando, D. et al. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev. 16, 1466–1471 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Mahon, P. C., Hirota, K. & Semenza, G. L. FIH-1: a novel protein that interacts with HIF-1α and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev. 15, 2675–2686 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Hewitson, K. S. et al. Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family. J. Biol. Chem. 277, 26351–26355 (2002).

    Article  CAS  PubMed  Google Scholar 

  152. Simon, M. C. & Keith, B. The role of oxygen availability in embryonic development and stem cell function. Nature Rev. Mol. Cell Biol. 9, 285–296 (2008).

    Article  CAS  Google Scholar 

  153. Mazumdar, J. et al. O2 regulates stem cells through Wnt/β-catenin signalling. Nature Cell Biol. 12, 1007–1013 (2010).

    Article  CAS  PubMed  Google Scholar 

  154. Kaidi, A., Williams, A. C. & Paraskeva, C. Interaction between β-catenin and HIF-1 promotes cellular adaptation to hypoxia. Nature Cell Biol. 9, 210–217 (2007).

    Article  CAS  PubMed  Google Scholar 

  155. Gustafsson, M. V. et al. Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev. Cell 9, 617–628 (2005).

    Article  CAS  PubMed  Google Scholar 

  156. Bertout, J. A. et al. Heterozygosity for hypoxia inducible factor 1α decreases the incidence of thymic lymphomas in a p53 mutant mouse model. Cancer Res. 69, 3213–3220 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Pietras, A. et al. HIF-2α maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells. Proc. Natl Acad. Sci. USA 106, 16805–16810 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Covello, K. L. et al. HIF-2α regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes Dev. 20, 557–570 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Gilbertson, R. J. & Rich, J. N. Making a tumour's bed: glioblastoma stem cells and the vascular niche. Nature Rev. Cancer 7, 733–736 (2007).

    Article  CAS  Google Scholar 

  160. Semenza, G. L. HIF-1: upstream and downstream of cancer metabolism. Curr. Opin. Genet. Dev. 20, 51–56 (2010).

    Article  CAS  PubMed  Google Scholar 

  161. Korkolopoulou, P. et al. Hypoxia-inducible factor 1α/vascular endothelial growth factor axis in astrocytomas. Associations with microvessel morphometry, proliferation and prognosis. Neuropathol. Appl. Neurobiol. 30, 267–278 (2004).

    Article  CAS  PubMed  Google Scholar 

  162. Scrideli, C. A. et al. Prognostic significance of co-overexpression of the EGFR/IGFBP-2/HIF-2A genes in astrocytomas. J. Neurooncol. 83, 233–239 (2007).

    Article  CAS  PubMed  Google Scholar 

  163. Theodoropoulos, V. E. et al. Hypoxia-inducible factor 1α expression correlates with angiogenesis and unfavorable prognosis in bladder cancer. Eur. Urol. 46, 200–208 (2004).

    Article  CAS  PubMed  Google Scholar 

  164. Yamamoto, Y. et al. Hypoxia-inducible factor 1α is closely linked to an aggressive phenotype in breast cancer. Breast Cancer Res. Treat. 110, 465–475 (2008).

    Article  CAS  PubMed  Google Scholar 

  165. Helczynska, K. et al. Hypoxia-inducible factor-2α correlates to distant recurrence and poor outcome in invasive breast cancer. Cancer Res. 68, 9212–9220 (2008).

    Article  CAS  PubMed  Google Scholar 

  166. Birner, P. et al. Overexpression of hypoxia-inducible factor 1α is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. Cancer Res. 60, 4693–4696 (2000).

    CAS  PubMed  Google Scholar 

  167. Kawanaka, T. et al. Prognostic significance of HIF-2α expression on tumor infiltrating macrophages in patients with uterine cervical cancer undergoing radiotherapy. J. Med. Invest. 55, 78–86 (2008).

    Article  PubMed  Google Scholar 

  168. Yoshimura, H. et al. Prognostic impact of hypoxia-inducible factors 1α and 2α in colorectal cancer patients: correlation with tumor angiogenesis and cyclooxygenase-2 expression. Clin. Cancer Res. 10, 8554–8560 (2004).

    Article  CAS  PubMed  Google Scholar 

  169. Griffiths, E. A. et al. Hypoxia-inducible factor-1α expression in the gastric carcinogenesis sequence and its prognostic role in gastric and gastro-oesophageal adenocarcinomas. Br. J. Cancer 96, 95–103 (2007).

    Article  CAS  PubMed  Google Scholar 

  170. Griffiths, E. A. et al. Hypoxia-associated markers in gastric carcinogenesis and HIF-2α in gastric and gastro-oesophageal cancer prognosis. Br. J. Cancer 98, 965–973 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Mizokami, K., Kakeji, Y., Oda, S. & Maehara, Y. Relationship of hypoxia-inducible factor 1α and p21WAF1/CIP1 expression to cell apoptosis and clinical outcome in patients with gastric cancer. World J. Surg. Oncol. 4, 94 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  172. Takahashi, R. et al. Hypoxia-inducible factor-1α expression and angiogenesis in gastrointestinal stromal tumor of the stomach. Oncol. Rep. 10, 797–802 (2003).

    CAS  PubMed  Google Scholar 

  173. Koukourakis, M. I. et al. Hypoxia-inducible factor (HIF1A and HIF2A), angiogenesis, and chemoradiotherapy outcome of squamous cell head-and-neck cancer. Int. J. Radiat. Oncol. Biol. Phys. 53, 1192–1202 (2002).

    Article  CAS  PubMed  Google Scholar 

  174. Winter, S. C. et al. The relation between hypoxia-inducible factor (HIF)-1α and HIF-2α expression with anemia and outcome in surgically treated head and neck cancer. Cancer 107, 757–766 (2006).

    Article  CAS  PubMed  Google Scholar 

  175. Bangoura, G. et al. Prognostic significance of HIF-2α/EPAS1 expression in hepatocellular carcinoma. World J. Gastroenterol. 13, 3176–3182 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Giatromanolaki, A. et al. Relation of hypoxia inducible factor 1α and 2α in operable non-small cell lung cancer to angiogenic/molecular profile of tumours and survival. Br. J. Cancer 85, 881–890 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Kim, S. J. et al. Expression of HIF-1α, CA IX, VEGF, and MMP-9 in surgically resected non-small cell lung cancer. Lung Cancer 49, 325–335 (2005).

    Article  PubMed  Google Scholar 

  178. Wu, X. H., Qian, C. & Yuan, K. Correlations of hypoxia-inducible factor-1α/hypoxia-inducible factor-2α expression with angiogenesis factors expression and prognosis in non-small cell lung cancer. Chin. Med. J. 124, 11–18 (2011).

    PubMed  Google Scholar 

  179. Giatromanolaki, A. et al. Hypoxia-inducible factors 1α and 2α are related to vascular endothelial growth factor expression and a poorer prognosis in nodular malignant melanomas of the skin. Melanoma Res. 13, 493–501 (2003).

    Article  CAS  PubMed  Google Scholar 

  180. Noguera, R. et al. HIF-1α and HIF-2α are differentially regulated in vivo in neuroblastoma: high HIF-1α correlates negatively to advanced clinical stage and tumor vascularization. Clin. Cancer Res. 15, 7130–7136 (2009).

    Article  CAS  PubMed  Google Scholar 

  181. Daponte, A. et al. Prognostic significance of Hypoxia-Inducible Factor 1α (HIF-1α) expression in serous ovarian cancer: an immunohistochemical study. BMC Cancer 8, 335 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  182. Osada, R. et al. Expression of hypoxia-inducible factor 1α, hypoxia-inducible factor 2α, and von Hippel-Lindau protein in epithelial ovarian neoplasms and allelic loss of von Hippel-Lindau gene: nuclear expression of hypoxia-inducible factor 1α is an independent prognostic factor in ovarian carcinoma. Hum. Pathol. 38, 1310–1320 (2007).

    Article  CAS  PubMed  Google Scholar 

  183. Sun, H. C. et al. Expression of hypoxia-inducible factor-1α and associated proteins in pancreatic ductal adenocarcinoma and their impact on prognosis. Int. J. Oncol. 30, 1359–1367 (2007).

    CAS  PubMed  Google Scholar 

  184. Shibaji, T. et al. Prognostic significance of HIF-1α overexpression in human pancreatic cancer. Anticancer Res. 23, 4721–4727 (2003).

    CAS  PubMed  Google Scholar 

  185. Nanni, S. et al. Endothelial NOS, estrogen receptor β, and HIFs cooperate in the activation of a prognostic transcriptional pattern in aggressive human prostate cancer. J. Clin. Invest. 119, 1093–1108 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Lidgren, A. et al. The expression of hypoxia-inducible factor 1α is a favorable independent prognostic factor in renal cell carcinoma. Clin. Cancer Res. 11, 1129–1135 (2005).

    CAS  PubMed  Google Scholar 

  187. Klatte, T. et al. Hypoxia-inducible factor 1α in clear cell renal cell carcinoma. Clin. Cancer Res. 13, 7388–7393 (2007).

    Article  CAS  PubMed  Google Scholar 

  188. Kapitsinou, P. P. et al. Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia. Blood 116, 3039–3048 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Gunaratnam, L. et al. Hypoxia inducible factor activates the transforming growth factor-α/epidermal growth factor receptor growth stimulatory pathway in VHL−/− renal cell carcinoma cells. J. Biol. Chem. 278, 44966–44974 (2003).

    Article  CAS  PubMed  Google Scholar 

  190. Carmeliet, P. et al. Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394, 485–490 (1998).

    Article  CAS  PubMed  Google Scholar 

  191. 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 

  192. Kondo, K., Klco, J., Nakamura, E., Lechpammer, M. & Kaelin, W. G. Jr. Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell 1, 237–246 (2002).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank F. Tucker for expert assistance with the figures and manuscript preparation, and apologize to colleagues whose work they were unable to cite because of space limitations.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M. Celeste Simon.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

National Cancer Institute Drug Dictionary

daunorubicin

doxorubicin

echinomycin

erlotinib

everolimus

gefitinib

imatinib

PX-478

rapamycin

temsirolimus

topotecan

trastuzumab

Glossary

Basic helix-loop-helix–PER–ARNT–SIM

(bHLH–PAS). A bHLH domain is a conserved DNA binding domain found in a number of transcription factors. PAS is a protein–protein dimerization domain that is related to the conserved signal sensing protein motifs in the Drosophila melanogaster period (PER), the mammalian aryl hydrocarbon receptor nuclear translocator (ARNT) and D. melanogaster single-minded (SIM) proteins.

ARNT

The aryl hydrocarbon receptor nuclear translocator (ARNT) was originally identified as the binding partner for the aryl hydrocarbon receptor (AHR). ARNT was later shown to be identical to HIF1β, the obligate binding partner for HIF1α and HIF2α.

Autochthonous

This term means 'originating where found'. It refers to tumours that arise in the tissues in which they are usually detected; for example, thymic lymphomas developing in the thymus of genetically engineered animals.

Angiogenic switch

The formation of new blood vessels when tumour growth progresses beyond the diffusion limits of oxygen and blood-borne nutrients.

Radioresistance

Tumours that exhibit resistance to common forms of ionizing radiation treatment.

Autophagy

A recycling process within lysosomes whereby cells liberate intracellular stores of nutrients by degrading cytoplasmic proteins and organelles.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Keith, B., Johnson, R. & Simon, M. HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer 12, 9–22 (2012). https://doi.org/10.1038/nrc3183

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc3183

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer