Vol 71, No 5 (2020)
Review paper
Published online: 2020-10-30

open access

Page views 1460
Article views/downloads 1382
Get Citation

Connect on Social Media

Connect on Social Media

An overview of biological research on hypoxia-inducible factors (HIFs)

Zhe Liu1, Zixuan Wu2, Yuxin Fan1, Yudong Fang1
Pubmed: 33202030
Endokrynol Pol 2020;71(5):432-440.


Hypoxia-inducible factors (HIFs), as a family of transcription factors involved in the cellular response to hypoxia, are key regulatory factors in the regulation mechanism of an organism’s response to hypoxia. A large number of studies have shown that HIFs are closely related to the angiogenesis, erythropoiesis, cell metabolism, and autophagy of organisms, as well as the occurrence and development of tumours. Therefore, it is of great significance to further study HIFs to understand and treat tumours or other related diseases. This paper summarises the structure, oxygen-dependent degradation mechanism, non-oxygen-dependent degradation mechanism, transcriptional activation mechanism, relevant signalling pathways, and inhibitors of HIFs, in order to provide new clues for the treatment of tumour, vascular, and other related diseases. 

Article available in PDF format

View PDF Download PDF file


  1. Storz G, Imlay JA. Oxidative stress. Curr Opin Microbiol. 1999; 2(2): 188–194.
  2. Wiesener MS, Maxwell PH. HIF and oxygen sensing; as important to life as the air we breathe? Ann Med. 2003; 35(3): 183–190.
  3. Semenza GL. HIF-1 and human disease: one highly involved factor. Genes Dev. 2000; 14(16): 1983–1991.
  4. Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol. 1992; 12(12): 5447–5454.
  5. Wang GL, Semenza GL. Characterization of hypoxia-inducible factor 1 and regulation of DNA binding activity by hypoxia. J Biol Chem. 1993; 268(29): 21513–21518.
  6. Wang GL, Semenza GL. Purification and characterization of hypoxia-inducible factor 1. J Biol Chem. 1995; 270(3): 1230–1237.
  7. Wang GL, Semenza GL. Purification and characterization of hypoxia-inducible factor 1. J Biol Chem. 1995; 270(3): 1230–1237.
  8. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003; 3(10): 721–732.
  9. Sharp FR, Bernaudin M. HIF1 and oxygen sensing in the brain. Nat Rev Neurosci. 2004; 5(6): 437–448.
  10. Sharp F, Bernaudin M. HIF1 and oxygen sensing in the brain. Nat Rev Neurosci. 2004; 5(6): 437–448.
  11. Semenza GL. Targeting hypoxia-inducible factor 1 to stimulate tissue vascularization. J Investig Med. 2016; 64(2): 361–363.
  12. Semenza GL. Hypoxia-inducible factors in physiology and medicine. Cell. 2012; 148(3): 399–408.
  13. Semenza GL. Vascular responses to hypoxia and ischemia. Arterioscler Thromb Vasc Biol. 2010; 30(4): 648–652.
  14. Hirao M, Hashimoto J, Yamasaki N, et al. Oxygen tension is an important mediator of the transformation of osteoblasts to osteocytes. J Bone Miner Metab. 2007; 25(5): 266–276.
  15. Pinheiro C, Miranda-Gonçalves V, Longatto-Filho A, et al. The metabolic microenvironment of melanomas: Prognostic value of MCT1 and MCT4. Cell Cycle. 2016; 15(11): 1462–1470.
  16. Serocki M, Bartoszewska S, Janaszak-Jasiecka A, et al. miRNAs regulate the HIF switch during hypoxia: a novel therapeutic target. Angiogenesis. 2018; 21(2): 183–202.
  17. Klaus A, Fathi O, Tatjana TW, et al. Expression of Hypoxia-Associated Protein HIF-1α in Follicular Thyroid Cancer is Associated with Distant Metastasis. Pathol Oncol Res. 2018; 24(2): 289–296.
  18. Zhu Gh, Huang C, Feng Zz, et al. Hypoxia-induced snail expression through transcriptional regulation by HIF-1α in pancreatic cancer cells. Dig Dis Sci. 2013; 58(12): 3503–3515.
  19. Duan C. Hypoxia-inducible factor 3 biology: complexities and emerging themes. Am J Physiol Cell Physiol. 2016; 310(4): C260–C269.
  20. Lando D, Gorman JJ, Whitelaw ML, et al. Oxygen-dependent regulation of hypoxia-inducible factors by prolyl and asparaginyl hydroxylation. Eur J Biochem. 2003; 270(5): 781–790.
  21. Wang GL, Semenza GL. Purification and characterization of hypoxia-inducible factor 1. J Biol Chem. 1995; 270(3): 1230–1237.
  22. Jiang BH, Zheng JZ, Leung SW, et al. Transactivation and inhibitory domains of hypoxia-inducible factor 1alpha. Modulation of transcriptional activity by oxygen tension. J Biol Chem. 1997; 272(31): 19253–19260.
  23. Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science. 2001; 294(5545): 1337–1340.
  24. Jaakkola P, Mole DR, Tian YM, et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001; 292(5516): 468–472.
  25. Lee JW, Bae SH, Jeong JW, et al. Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions. Exp Mol Med. 2004; 36(1): 1–12.
  26. Mahon PC, Hirota K, Semenza GL. FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev. 2001; 15(20): 2675–2686.
  27. Shi H, Wu Y, et al. Ubiquitin ligase Siah1 promotes the migration and invasion of human glioma cells by regulating HIF-1α signaling under hypoxia. Oncol Rep. 2015; 33(3): 1185–1190.
  28. Wiesener MS, Turley H, Allen WE, et al. Induction of endothelial PAS domain protein-1 by hypoxia: characterization and comparison with hypoxia-inducible factor-1alpha. Blood. 1998; 92(7): 2260–2268.
  29. Epstein AC, Gleadle JM, McNeill LA, et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell. 2001; 107(1): 43–54.
  30. Epstein AC, Gleadle JM, McNeill LA, et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell. 2001; 107(1): 43–54.
  31. Gu BJ, Zhang W, Worthington RA, et al. A Glu-496 to Ala polymorphism leads to loss of function of the human P2X7 receptor. J Biol Chem. 2001; 276(14): 11135–11142.
  32. Xilouri M, Stefanis L. Chaperone mediated autophagy in aging: Starve to prosper. Ageing Res Rev. 2016; 32: 13–21.
  33. Hubbi ME, Hu H, Ahmed I, et al. Chaperone-mediated autophagy targets hypoxia-inducible factor-1α (HIF-1α) for lysosomal degradation. J Biol Chem. 2013; 288(15): 10703–10714.
  34. Adam MG, Matt S, Christian S, et al. SIAH ubiquitin ligases regulate breast cancer cell migration and invasion independent of the oxygen status. Cell Cycle. 2015; 14(23): 3734–3747.
  35. Semenza GL. HIF-1, O(2), and the 3 PHDs: how animal cells signal hypoxia to the nucleus. Cell. 2001; 107(1): 1–3.
  36. Semenza GL. Physiology meets biophysics: Visualizing the interaction of hypoxia-inducible factor 1  with p300 and CBP. Proc Natl Acad Sci USA. 2002; 99(18): 11570–11572.
  37. Lando D, Peet DJ, Gorman JJ, et al. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev. 2002; 16(12): 1466–1471.
  38. Martin A, Patlan MC, Flores MR. The Role of Hypoxia-Inducible Factors in Cancer Resistance. J Cell Signal. 2017; 2(1): 154.
  39. Lando D, Peet DJ, Whelan DA, et al. Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science. 2002; 295(5556): 858–861.
  40. Kung AL, Wang S, Klco JM, et al. Suppression of tumor growth through disruption of hypoxia-inducible transcription. Nat Med. 2000; 6(12): 1335–1340.
  41. Mylonis I, Chachami G, Samiotaki M, et al. Identification of MAPK phosphorylation sites and their role in the localization and activity of hypoxia-inducible factor-1alpha. J Biol Chem. 2006; 281(44): 33095–33106.
  42. Kietzmann T, Mennerich D, Dimova EY. Hypoxia-Inducible Factors (HIFs) and Phosphorylation: Impact on Stability, Localization, and Transactivity. Front Cell Dev Biol. 2016; 4: 11.
  43. Joo HY, Yun M, Jeong J, et al. SIRT1 deacetylates and stabilizes hypoxia-inducible factor-1α (HIF-1α) via direct interactions during hypoxia. Biochem Biophys Res Commun. 2015; 462(4): 294–300.
  44. Lee SoD, Kim W, Jeong JW, et al. AK-1, a SIRT2 inhibitor, destabilizes HIF-1α and diminishes its transcriptional activity during hypoxia. Cancer Lett. 2016; 373(1): 138–145.
  45. Subbaramaiah K, Iyengar NM, Morrow M, et al. Prostaglandin E down-regulates sirtuin 1 (SIRT1), leading to elevated levels of aromatase, providing insights into the obesity-breast cancer connection. J Biol Chem. 2019; 294(1): 361–371.
  46. Calgani A, Delle Monache S, Cesare P, et al. Leptin contributes to long-term stabilization of HIF-1α in cancer cells subjected to oxygen limiting conditions. Cancer Lett. 2016; 376(1): 1–9.
  47. Hubbi ME, Hu H, Gilkes DM, et al. Sirtuin-7 inhibits the activity of hypoxia-inducible factors. J Biol Chem. 2013; 288(29): 20768–20775.
  48. Schöning JP, Monteiro M, Gu W. Drug resistance and cancer stem cells: the shared but distinct roles of hypoxia-inducible factors HIF1α and HIF2α. Clin Exp Pharmacol Physiol. 2017; 44(2): 153–161.
  49. Chen J, Bai M, Ning C, et al. Gankyrin facilitates follicle-stimulating hormone-driven ovarian cancer cell proliferation through the PI3K/AKT/HIF-1α/cyclin D1 pathway. Oncogene. 2016; 35(19): 2506–2517.
  50. Wang Hu, Zhao Li, Zhu LT, et al. Wogonin reverses hypoxia resistance of human colon cancer HCT116 cells via downregulation of HIF-1α and glycolysis, by inhibiting PI3K/Akt signaling pathway. Mol Carcinog. 2014; 53 Suppl 1: E107–E118.
  51. Shi Yh, Wang Yx, You Jf, et al. [Activation of HIF-1 by bFGF in breast cancer: role of PI-3K and MEK1/ERK pathways]. Zhonghua Yi Xue Za Zhi. 2004; 84(22): 1899–1903.
  52. Shi YH, Wang YX, Bingle L, et al. In vitro study of HIF-1 activation and VEGF release by bFGF in the T47D breast cancer cell line under normoxic conditions: involvement of PI-3K/Akt and MEK1/ERK pathways. J Pathol. 2005; 205(4): 530–536.
  53. Zhang Q, Oh CK, Messadi DV, et al. Hypoxia-induced HIF-1 alpha accumulation is augmented in a co-culture of keloid fibroblasts and human mast cells: involvement of ERK1/2 and PI-3K/Akt. Exp Cell Res. 2006; 312(2): 145–155.
  54. Ao Q, Su W, Guo S, et al. SENP1 desensitizes hypoxic ovarian cancer cells to cisplatin by up-regulating HIF-1α. Sci Rep. 2015; 5: 16396.
  55. Zhou J, Sun C. SENP1/HIF-1α axis works in angiogenesis of human dental pulp stem cells. J Biochem Mol Toxicol. 2020; 34(3): e22436.
  56. Wang X, Liang X, Liang H, et al. SENP1/HIF-1α feedback loop modulates hypoxia-induced cell proliferation, invasion, and EMT in human osteosarcoma cells. J Cell Biochem. 2018; 119(2): 1819–1826.
  57. Cui CP, Wong CCL, Kai AKL, et al. SENP1 promotes hypoxia-induced cancer stemness by HIF-1α deSUMOylation and SENP1/HIF-1α positive feedback loop. Gut. 2017; 66(12): 2149–2159.
  58. Wu H, Huang S, Chen Z, et al. Hypoxia-induced autophagy contributes to the invasion of salivary adenoid cystic carcinoma through the HIF-1α/BNIP3 signaling pathway. Mol Med Rep. 2015; 12(5): 6467–6474.
  59. Zhang Y, Liu D, Hu H, et al. HIF-1α/BNIP3 signaling pathway-induced-autophagy plays protective role during myocardial ischemia-reperfusion injury. Biomed Pharmacother. 2019; 120: 109464.
  60. Peng Y, Fang Z, Liu M, et al. Testosterone induces renal tubular epithelial cell death through the HIF-1α/BNIP3 pathway. J Transl Med. 2019; 17(1): 62.
  61. Liu XW, Lu MK, Zhong HT, et al. Panax Notoginseng Saponins Attenuate Myocardial Ischemia-Reperfusion Injury Through the HIF-1α/BNIP3 Pathway of Autophagy. J Cardiovasc Pharmacol. 2019; 73(2): 92–99.
  62. Wu H, Huang S, Chen Z, et al. Hypoxia-induced autophagy contributes to the invasion of salivary adenoid cystic carcinoma through the HIF-1α/BNIP3 signaling pathway. Mol Med Rep. 2015; 12(5): 6467–6474.
  63. Zhao Yi, Chen G, Zhang W, et al. Autophagy regulates hypoxia-induced osteoclastogenesis through the HIF-1α/BNIP3 signaling pathway. J Cell Physiol. 2012; 227(2): 639–648.
  64. Berra E, Milanini J, Richard D, et al. Signaling angiogenesis via p42/p44 MAP kinase and hypoxia. Biochem Pharmacol. 2000; 60(8): 1171–1178.
  65. Huang CY, Hsieh YL, Ju DT, et al. Attenuation of Magnesium Sulfate on CoCl₂-Induced Cell Death by Activating ERK1/2/MAPK and Inhibiting HIF-1α via Mitochondrial Apoptotic Signaling Suppression in a Neuronal Cell Line. Chin J Physiol. 2015; 58(4): 244–253.
  66. Minet E, Arnould T, Michel G, et al. ERK activation upon hypoxia: involvement in HIF-1 activation. FEBS Lett. 2000; 468(1): 53–58.
  67. Hannken T, Schroeder R, Zahner G. Reactive oxygen species stimulate p44/42 mitogen-activated protein kinase and induce p27(Kip1): role in angiotensin II-mediated hypertrophy of proximal tubular cells. J Am Soc Nephrol. 2000; 11: 1387–1397.
  68. Guan R, Wang J, Li Z, et al. Sodium Tanshinone IIA Sulfonate Decreases Cigarette Smoke-Induced Inflammation and Oxidative Stress via Blocking the Activation of MAPK/HIF-1α Signaling Pathway. Front Pharmacol. 2018; 9: 263.
  69. Gao L, Wu Gj, Liu B, et al. Up-regulation of pVHL along with down-regulation of HIF-1α by NDRG2 expression attenuates proliferation and invasion in renal cancer cells. PLoS One. 2013; 8(12): e84127.
  70. Yokoe S, Nakagawa T, Kojima Y, et al. Indomethacin-induced intestinal epithelial cell damage is mediated by pVHL activation through the degradation of collagen I and HIF-1α. Biochem Biophys Res Commun. 2015; 468(4): 671–676.
  71. Minet E, Mottet D, Michel G, et al. Hypoxia-induced activation of HIF-1: role of HIF-1alpha-Hsp90 interaction. FEBS Lett. 1999; 460(2): 251–256.
  72. Liu NN, Zhao N, Cai Na. The effect and mechanism of celecoxib in hypoxia-induced survivin up-regulation in HUVECs. Cell Physiol Biochem. 2015; 37(3): 991–1001.
  73. Xu WN, Zheng HL, Yang RZ, et al. HIF-1α Regulates Glucocorticoid-Induced Osteoporosis Through PDK1/AKT/mTOR Signaling Pathway. Front Endocrinol (Lausanne). 2019; 10: 922.
  74. Chi Y, Luo Q, Song Y, et al. Circular RNA circPIP5K1A promotes non-small cell lung cancer proliferation and metastasis through miR-600/HIF-1α regulation. J Cell Biochem. 2019; 120(11): 19019–19030.
  75. Shen Y, Chen G, Zhuang L, et al. ARHGAP4 mediates the Warburg effect in pancreatic cancer through the mTOR and HIF-1α signaling pathways. Onco Targets Ther. 2019; 12: 5003–5012.
  76. Shen B, Mei M, Pu Y, et al. Necrostatin-1 Attenuates Renal Ischemia and Reperfusion Injury via Meditation of HIF-1α/mir-26a/TRPC6/PARP1 Signaling. Mol Ther Nucleic Acids. 2019; 17: 701–713.
  77. Yang R, Zhu Yi, Wang Y, et al. HIF-1α/PDK4/autophagy pathway protects against advanced glycation end-products induced vascular smooth muscle cell calcification. Biochem Biophys Res Commun. 2019; 517(3): 470–476.
  78. Zhu L, Mu J, Wu Y, et al. Role of HIF-1α in Cold Ischemia Injury of Rat Donor Heart Via the miR-21/PDCD4 Pathway. Transplant Proc. 2020; 52(1): 383–391.
  79. Gai X, Zhou P, Xu M, et al. Hyperactivation of IL-6/STAT3 pathway leaded to the poor prognosis of post-TACE HCCs by HIF-1α/SNAI1 axis-induced epithelial to mesenchymal transition. J Cancer. 2020; 11(3): 570–582.
  80. Liu H, Shi C, Deng Y. MALAT1 affects hypoxia-induced vascular endothelial cell injury and autophagy by regulating miR-19b-3p/HIF-1α axis. Mol Cell Biochem. 2020; 466(1-2): 25–34.
  81. Yu LM, Zhang WH, Han XX, et al. Hypoxia-Induced ROS Contribute to Myoblast Pyroptosis during Obstructive Sleep Apnea via the NF-B/HIF-1 Signaling Pathway. Oxid Med Cell Longev. 2019; 2019: 4596368.
  82. Jeong W, Rapisarda A, Park SR, et al. Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors. Cancer Chemother Pharmacol. 2014; 73(2): 343–348.
  83. Zhang H, Pu J, Qi T, et al. MicroRNA-145 inhibits the growth, invasion, metastasis and angiogenesis of neuroblastoma cells through targeting hypoxia-inducible factor 2 alpha. Oncogene. 2014; 33(3): 387–397.
  84. Qu H, Zheng L, Song H, et al. microRNA-558 facilitates the expression of hypoxia-inducible factor 2 alpha through binding to 5'-untranslated region in neuroblastoma. Oncotarget. 2016; 7(26): 40657–40673.
  85. Hutt DM, Roth DM, Vignaud H, et al. The histone deacetylase inhibitor, Vorinostat, represses hypoxia inducible factor 1 alpha expression through translational inhibition. PLoS One. 2014; 9(8): e106224.
  86. Coltella N, Valsecchi R, Ponente M, et al. Synergistic Leukemia Eradication by Combined Treatment with Retinoic Acid and HIF Inhibition by EZN-2208 (PEG-SN38) in Preclinical Models of PML-RARα and PLZF-RARα-Driven Leukemia. Clin Cancer Res. 2015; 21(16): 3685–3694.
  87. Ma Li, Li G, Zhu H, et al. 2-Methoxyestradiol synergizes with sorafenib to suppress hepatocellular carcinoma by simultaneously dysregulating hypoxia-inducible factor-1 and -2. Cancer Lett. 2014; 355(1): 96–105.
  88. Shukla SK, Purohit V, Mehla K, et al. MUC1 and HIF-1alpha Signaling Crosstalk Induces Anabolic Glucose Metabolism to Impart Gemcitabine Resistance to Pancreatic Cancer. Cancer Cell. 2017; 32(1): 71–87.e7.
  89. Yu T, Tang Bo, Sun X. Development of Inhibitors Targeting Hypoxia-Inducible Factor 1 and 2 for Cancer Therapy. Yonsei Med J. 2017; 58(3): 489–496.
  90. Wu D, Potluri N, Lu J, et al. Structural integration in hypoxia-inducible factors. Nature. 2015; 524(7565): 303–308.
  91. Miranda E, Nordgren IK, Male AL, et al. A cyclic peptide inhibitor of HIF-1 heterodimerization that inhibits hypoxia signaling in cancer cells. J Am Chem Soc. 2013; 135(28): 10418–10425.
  92. Scheuermann TH, Li Q, Ma HW, et al. Allosteric inhibition of hypoxia inducible factor-2 with small molecules. Nat Chem Biol. 2013; 9(4): 271–276.
  93. Wilkins SE, Abboud MI, Hancock RL, et al. Targeting Protein-Protein Interactions in the HIF System. ChemMedChem. 2016; 11(8): 773–786.
  94. Latha MS, Saddala MS. Molecular docking based screening of a simulated HIF-1 protein model for potential inhibitors. Bioinformation. 2017; 13(11): 388–393.
  95. Portugal J. Challenging transcription by DNA-binding antitumor drugs. Biochem Pharmacol. 2018; 155: 336–345.
  96. Jayatunga MKP, Thompson S, McKee TC, et al. Inhibition of the HIF1α-p300 interaction by quinone- and indandione-mediated ejection of structural Zn(II). Eur J Med Chem. 2015; 94: 509–516.
  97. Reece KM, Richardson ED, Cook KM, et al. Epidithiodiketopiperazines (ETPs) exhibit in vitro antiangiogenic and in vivo antitumor activity by disrupting the HIF-1α/p300 complex in a preclinical model of prostate cancer. Mol Cancer. 2014; 13: 91.
  98. Zimna A, Kurpisz M. Hypoxia-Inducible Factor-1 in Physiological and Pathophysiological Angiogenesis: Applications and Therapies. Biomed Res Int. 2015; 2015: 549412.
  99. Masoud GN, Wang J, Chen J, et al. Design, Synthesis and Biological Evaluation of Novel HIF1α Inhibitors. Anticancer Res. 2015; 35(7): 3849–3859.
  100. Jiang L, Shi S, Shi Q, et al. Similarity in the functions of HIF-1α and HIF-2α proteins in cervical cancer cells. Oncol Lett. 2017; 14(5): 5643–5651.
  101. Guan Z, Ding C, Du Y, et al. HAF drives the switch of HIF-1α to HIF-2α by activating the NF-κB pathway, leading to malignant behavior of T24 bladder cancer cells. Int J Oncol. 2014; 44(2): 393–402.
  102. Martínez-Sáez O, Gajate Borau P, Alonso-Gordoa T, et al. Targeting HIF-2 α in clear cell renal cell carcinoma: A promising therapeutic strategy. Crit Rev Oncol Hematol. 2017; 111: 117–123.
  103. Taylor CT, Colgan SP. Regulation of immunity and inflammation by hypoxia in immunological niches. Nat Rev Immunol. 2017; 17(12): 774–785.