Visn. Nac. Akad. Nauk Ukr. 2019. (12): 3-19
https://doi.org/10.15407/visn2019.12.003

S.I. Romaniuk, S.V. Komisarenko
Palladin Institute of Biochemistry of the National Academy of Sciences of Ukraine, Kyiv

MECHANISMS OF CELL ADAPTATION TO HYPOXIA, OR HOW TO "BLOCK OXYGEN" TO A MALIGNANT TUMOR
Nobel Prize in Physiology or Medicine for 2019

The 2019 Nobel Prize in Physiology or Medicine was awarded to two American scientists — William G. Kaelin, Jr. from Harvard University and Gregg L. Semenza from Johns Hopkins University — and British researcher Sir Peter J. Ratcliffe of Oxford University “for their discoveries of how cells sense and adapt to oxygen availability.” The work of this year's Nobel laureates laid the groundwork for understanding how oxygen levels affect cellular metabolism and physiological functions. Their research paves the way for new strategies to fight anemia, cancer and many other diseases.

Language of article: ukrainian

Full text (PDF)

REFERENCES

  1. Citation Laureates 2019.
    https://clarivate.com/webofsciencegroup/wp-content/uploads/sites/2/dlm_uploads/2019/09/Citation_Laureates_2019.pdf
  2. The Nobel Prize in Physiology or Medicine 2019. Press release. https://www.nobelprize.org/prizes/medicine/2019/press-release/
  3. William Kaelin Jr. Wikipedia. https://en.wikipedia.org/wiki/William_Kaelin_Jr.
  4. Carolyn Kaelin. Wikipedia. https://en.wikipedia.org/wiki/Carolyn_Kaelin
  5. Peter J. Ratcliffe. Wikipedia. https://en.wikipedia.org/wiki/Peter_J._Ratcliffe
  6. Gregg L. Semenza. Wikipedia. https://en.wikipedia.org/wiki/Gregg_L._Semenza
  7. Johnson R.S. Scientific Background. How cells sense and adapt to oxygen availability. https://www.nobelprize.org/prizes/medicine/2019/advanced-information/
  8. Belitser V.A., Tsybakova E.T. On the mechanism of phosphorylation associated with respiration. Biochemistry. 1939. 4(5): 516.
  9. Miyake T., Kung C.K., Goldwasser E. Purification of human erythropoietin. J. Biol. Chem. 1977. 252(15): 5558.
  10. Bondurant M.C., Koury M.J. Anemia induces accumulation of erythropoietin mRNA in the kidney and liver. Mol. Cell Biol. 1986. 6(7): 2731. DOI: https://doi.org/10.1128/MCB.6.7.2731
  11. Semenza G.L., Nejfelt M.K., Chi S.M., Antonarakis S.E. Hypoxia-inducible nuclear factors bind to an enhancer element located 3' to the human erythropoietin gene. Proc. Natl. Acad. Sci. USA. 1991. 88(13): 5680. DOI: https://doi.org/10.1073/pnas.88.13.5680
  12. Beck I., Ramirez S., Weinmann R., Caro J. Enhancer element at the 3'-flanking region controls transcriptional response to hypoxia in the human erythropoietin gene. J. Biol. Chem. 1991. 266(24): 15563.
  13. Semenza G.L., Wang G.L. 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. DOI: https://doi.org/10.1128/mcb.12.12.5447
  14. Maxwell P.H., Pugh C.W., Ratcliffe P.J. Inducible operation of the erythropoietin 3' enhancer in multiple cell lines: evidence for a widespread oxygen-sensing mechanism. Proc. Natl. Acad. Sci. USA. 1993. 90(6): 2423. DOI: https://doi.org/10.1073/pnas.90.6.2423
  15. Wang G.L., Semenza G.L. General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc. Natl. Acad. Sci. USA. 1993. 90(9): 4304. DOI: https://doi.org/10.1073/pnas.90.9.4304
  16. Wang G.L., Semenza G.L. Purification and characterization of hypoxia-inducible factor 1. J. Biol. Chem. 1995. 270(3): 1230. DOI: https://doi.org/ 10.1074/jbc.270.3.1230
  17. 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. 1995. 92(12): 5510. DOI: https://doi.org/10.1073/pnas.92.12.5510
  18. Ema M., Taya S., Yokotani N., Sogawa K., Matsuda Y., Fujii-Kuriyama Y. A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proc. Natl. Acad. Sci. USA. 1997. 94(9): 4273. DOI: https://doi.org/10.1073/pnas.94.9.4273
  19. Flamme I., Frohlich T., von Reutern M., Kappel A., Damert A., Risau W. HRF, a putative basic helixloop-helix-PAS-domain transcription factor is closely related to hypoxia-inducible factor-1 alpha and developmentally expressed in blood vessels. Mech. Dev. 1997. 63(1): 51. DOI: https://doi.org/10.1016/s0925-4773(97)00674-6
  20. Hogenesch J.B., Chan W.K., Jackiw V.H., Brown R.C., Gu Y.Z., Pray-Grant M., Perdew G.H., Bradfield C.A. Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway. J. Biol. Chem. 1997. 272(13): 8581. DOI: https://doi.org/10.1016/s0925-4773(97)00674-6
  21. Tian H., McKnight S.L., Russell D.W. Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev. 1997. 11(1): 72. DOI: https://doi.org/10.1101/gad.11.1.72
  22. Fandrey J. Oxygen-dependent and tissue-specific regulation of erythropoietin gene expression. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2004. 286(6), R977. DOI: https://doi.org/10.1152/ajpregu.00577.2003
  23. Pugh C.W., O'Rourke J.F., Nagao M., Gleadle J.M., Ratcliffe P.J. Activation of hypoxia-inducible factor-1; definition of regulatory domains within the alpha subunit. J. Biol. Chem. 1997. 272(17): 11205. DOI: https://doi.org/10.1074/jbc.272.17.11205
  24. Salceda S., Caro J. Hypoxia-inducible factor 1alpha (HIF-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J. Biol. Chem. 1997. 272(36): 22642. DOI: https://doi.org/10.1074/jbc.272.36.22642
  25. Huang L.E., Gu J., Schau M., Bunn H.F. Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc. Natl. Acad. Sci. USA. 1998. 95(14): 7987. DOI: https://doi.org/10.1073/pnas.95.14.7987
  26. Iliopoulos O., Kibel A., Gray S., Kaelin W.G. Jr. Tumour suppression by the human von Hippel-Lindau gene product. Nat. Med. 1995. 1(8): 822. DOI: https://doi.org/10.1038/nm0895-822
  27. Iliopoulos O., Levy A.P., Jiang C., Kaelin W.G. Jr., Goldberg M.A. Negative regulation of hypoxia inducible genes by the von Hippel-Lindau protein. Proc. Natl. Acad. Sci. USA. 1996. 93(20): 10595. DOI: https://doi.org/10.1073/pnas.93.20.10595
  28. Duan D.R., Pause A., Burgess W.H., Aso T., Chen D.Y., Garrett K.P., Conaway R.C., Conaway J.W., Linehan W.M., Klausner R.D. Inhibition of transcription elongation by the VHL tumor suppressor protein. Science. 1995. 269(5229): 1402. DOI: https://doi.org/10.1126/science.7660122
  29. Kibel A., Iliopoulos O., DeCaprio J.A., Kaelin W.G. Jr. Binding of the von Hippel-Lindau tumor suppressor protein to Elongin B and C. Science. 1995. 269(5229): 1444. DOI: https://doi.org/10.1126/science.7660130
  30. Pause A., Lee S., Worrell R.A., Chen D.Y., Burgess W.H., Linehan W.M., Klausner R.D. The von Hippel-Lindau tumor-suppressor gene product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins. Proc. Natl. Acad. Sci. USA. 1997. 94(6): 2156. DOI: https://doi.org/10.1073/pnas.94.6.2156
  31. Lonergan K.M., Iliopoulos O., Ohh M., Kamura T., Conaway R.C., Conaway J.W., Kaelin W.G. Jr. Regulation of hypoxia-inducible mRNAs by the von Hippel-Lindau tumor suppressor protein requires binding to complexes containing elongins B/C and Cul2. Mol. Cell. Biol. 1998. 18(2): 732. DOI: https://doi.org/10.1128/mcb.18.2.732
  32. Maxwell P.H., Wiesener M.S., Chang G.W., Clifford S.C., Vaux E.C., Cockman M.E., Wykoff C.C., Pugh C.W., Maher E.R., Ratcliffe P.J. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999. 399(6733): 271. DOI: https://doi.org/10.1038/20459
  33. Ivan M., Kondo K., Yang H., Kim W., Valiando J., Ohh M., Salic A., Asara J.M., Lane W.S., Kaelin W.G. Jr. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001. 292(5516): 464. DOI: https://doi.org/10.1126/science.1059817
  34. Jaakkola P., Mole D.R., Tian Y.M., Wilson M.I., Gielbert J., Gaskell S.J., Kriegsheim A., Hebestreit H.F., Mukherji M., Schofield C.J., Maxwell PH, Pugh CW, Ratcliffe PJ. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001. 292(5516): 468. DOI: https://doi.org/10.1126/science.1059796
  35. Bruick R.K., McKnight S.L. A conserved family of prolyl-4-hydroxylases that modify HIF. Science. 2001. 294(5545): 1337. DOI: https://doi.org/10.1126/science.1066373
  36. Epstein A.C., Gleadle J.M., McNeill L.A., Hewitson K.S., O'Rourke J., Mole D.R., Mukherji M., Metzen E., Wilson M.I., Dhanda A., Tian Y.M., Masson N., Hamilton D.L., Jaakkola P., Barstead R., Hodgkin J., Maxwell P.H., Pugh C.W., Schofield C.J., Ratcliffe P.J. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell. 2001. 107(1): 43. DOI: https://doi.org/10.1016/s0092-8674(01)00507-4
  37. Ivan M., Haberberger T., Gervasi D.C., Michelson K.S., Gunzler V., Kondo K., Yang H., Sorokina I., Conaway R.C., Conaway J.W., Kaelin W.G. Jr. Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor. Proc. Natl. Acad. Sci. USA. 2002. 99(21): 13459. DOI: https://doi.org/10.1073/pnas.192342099
  38. Mahon P.C., Hirota K., Semenza G.L. 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. DOI: https://doi.org/10.1101/gad.924501
  39. Lando D., Peet D.J., Whelan D.A., Gorman J.J., Whitelaw M.L. Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science. 2002. 295(5556): 858. DOI: https://doi.org/10.1126/science.1068592
  40. Ruas J.L., Berchner-Pfannschmidt U., Malik S., Gradin K., Fandrey J., Roeder R.G., Pereira T., Poellinger L. Complex regulation of the transactivation function of hypoxia-inducible factor-1 alpha by direct interaction with two distinct domains of the CREB-binding protein/p300. J. Biol. Chem. 2010. 285(4): 2601. DOI: https://doi.org/10.1074/jbc.M109.021824
  41. Li Z., Wang D., Na X., Schoen S.R., Messing E.M., Wu G. The VHL protein recruits a novel KRAB-A domain protein to repress HIF-1alpha transcriptional activity. EMBO J. 2003. 22(8):1857. DOI: https://doi.org/10.1093/emboj/cdg173
  42. Schödel J., Oikonomopoulos S., Ragoussis J., Pugh C.W., Ratcliffe P.J., Mole D.R. High-resolution genome-wide mapping of HIF-binding sites by ChIP-seq. Blood. 2011. 117(23): e207. DOI: https://doi.org/10.1182/blood-2010-10-314427
  43. Chavez J.C., Baranova O., Lin J., Pichiule P. The transcriptional activator hypoxia inducible factor 2 (HIF-2/EPAS-1) regulates the oxygen-dependent expression of erythropoietin in cortical astrocytes. J. Neurosci. 2006. 26(37): 9471. DOI: https://doi.org/10.1523/JNEUROSCI.2838-06.2006
  44. Dhillon S. Roxadustat: First Global Approval. Drugs. 2019. 79(5): 563. DOI: https://doi.org/10.1007/s40265-019-01077-1
  45. Frost J., Galdeano C., Soares P., Gadd M.S., Grzes K.M., Ellis L., Epemolu O., Shimamura S., Bantscheff M., Grandi P., Read K.D., Cantrell D.A., Rocha S., Ciulli A. Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition. Nat. Commun. 2016. 7: 13312. DOI: https://doi.org/10.1038/ncomms13312
  46. Zhang H., Qian D.Z., Tan Y.S., Lee K., Gao P., Ren Y.R., Rey S., Hammers H., Chang D., Pili R., Dang C.V., Liu J.O., Semenza G.L. Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor growth. Proc. Natl. Acad. Sci. USA. 2008. 105(50): 19579. DOI: https://doi.org/10.1073/pnas.0809763105
  47. Lopez-Lazaro M. Digoxin, HIF-1, and cancer. Proc. Natl. Acad. Sci. USA. 2009. 106(9): E26. DOI: https://doi.org/10.1073/pnas.0813047106
  48. Marshall D.J., Harried S.S., Murphy J.L., Hall C.A., Shekhani M.S., Pain C., Lyons C.A., Chillemi A., Malavasi F., Pearce H.L., Thorson J.S., Prudent J.R. Extracellular Antibody Drug Conjugates Exploiting the Proximity of Two Proteins. Mol. Ther. 2016. 24(10): 1760. DOI: https://doi.org/10.1038/mt.2016.119
  49. Scheepstra M., Hekking K.F.W., van Hijfte L., Folmer R.H.A. Bivalent Ligands for Protein Degradation in Drug Discovery. Comput. Struct. Biotechnol. J. 2019. 17: 160. DOI: https://doi.org/10.1016/j.csbj.2019.01.006
  50. Neklesa T., Snyder L.B., Willard R.R., Vitale N., Pizzano J., Gordon D.A., Bookbinder M., Macaluso J., Dong H., Ferraro C., Wang G., Wang J., Crews C.M., Houston J., Crew A.P., Taylor I. ARV-110: An oral androgen receptor PROTAC degrader for prostate cancer. Journal of Clinical Oncology. 2019. 37(7): 259. DOI: https://doi.org/10.1200/JCO.2019.37.7_suppl.259
  51. Maniaci C., Hughes S.J., Testa A., Chen W., Lamont D.J., Rocha S., Alessi D.R., Romeo R., Ciulli A. Homo-PROTACs: bivalent small-molecule dimerizers of the VHL E3 ubiquitin ligase to induce self-degradation. Nat. Commun. 2017. 8(1): 830. DOI: https://doi.org/10.1038/s41467-017-00954-1
  52. Zengerle M., Chan K.-H., Ciulli A. Selective small molecule induced degradation of the BET bromodomain protein BRD4. ACS Chem. Biol. 2015. 10(8): 1770. DOI: https://doi.org/10.1021/acschembio.5b00216
  53. da Motta L.L., Ledaki I., Purshouse K., Haider S., De Bastiani M.A., Baban D., Morotti M., Steers G., Wigfield S., Bridges E., Li J.L., Knapp S., Ebner D., Klamt F., Harris A.L., McIntyre A. The BET inhibitor JQ1 selectively impairs tumour response to hypoxia and downregulates CA9 and angiogenesis in triple negative breast cancer. Oncogene. 2017. 36(1): 122. DOI: https://doi.org/10.1038/onc.2016.184
  54. Pettersson M., Crews C.M. PROteolysis TArgeting Chimeras (PROTACs) - Past, present and future. Drug Discov. Today Technol. 2019. 31: 15. DOI: https://doi.org/10.1016/j.ddtec.2019.01.002
  55. Bayer, Arvinas Partner on PROTAC Joint Venture, Treatments for Cancer, CV, Gynecological Diseases. https://www.genengnews.com/news/bayer-arvinas-partner-on-protac-therapies-for-cancer-cv-gynecological-diseases/
  56. Dawson M.A. The cancer epigenome: concepts, challenges, and therapeutic opportunities. Science. 2017. 355(6330): 1147. DOI: https://doi.org/10.1126/science.aam7304
  57. Choudhry H., Harris A.L., McIntyre A. The tumour hypoxia induced non-coding transcriptome. Mol. Aspects Med. 2016. 47-48: 35. DOI: https://doi.org/10.1016/j.mam.2016.01.003
  58. Choudhry H., Harris A.L. Advances in Hypoxia-Inducible Factor Biology. Cell Metab. 2018. 27(2): 281. DOI: https://doi.org/10.1016/j.cmet.2017.10.005
  59. Zhao H., Yang L., Baddour J., Achreja A., Bernard V., Moss T., Marini J.C., Tudawe T., Seviour E.G., San Lucas F.A., Alvarez H., Gupta S., Maiti S.N., Cooper L., Peehl D., Ram P.T., Maitra A., Nagrath D. Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism. eLife. 2016. 5: e10250. DOI: https://doi.org/10.7554/eLife.10250
  60. Rong L., Li R., Li S., Luo R. Immunosuppression of breast cancer cells mediated by transforming growth factor-β in exosomes from cancer cells. Oncol. Lett. 2016. 11(1): 500. DOI: https://doi.org/10.3892/ol.2015.3841
  61. Berchem G., Noman M.Z., Bosseler M., Paggetti J., Baconnais S., Le Cam E., Nanbakhsh A., Moussay E., Mami-Chouaib F., Janji B., Chouaib S. Hypoxic tumor-derived microvesicles negatively regulate NK cell function by a mechanism involving TGF-β and miR23a transfer. OncoImmunology. 2015. 5(4): e1062968. DOI: https://doi.org/10.1080/2162402X.2015.1062968
  62. Fu L., Kettner N.M. The circadian clock in cancer development and therapy. Prog. Mol. Biol. Transl. Sci. 2013. 119: 221. DOI: https://doi.org/10.1016/B978-0-12-396971-2.00009-9
  63. Chilov D., Hofer T., Bauer C., Wenger R.H., Gassmann M. Hypoxia affects expression of circadian genes PER1 and CLOCK in mouse brain. FASEB J. 2001. 15(14): 2613. DOI: https://doi.org/10.1096/fj.01-0092com
  64. Ghorbel M.T., Coulson J.M., Murphy D. Cross-talk between hypoxic and circadian pathways: cooperative roles for hypoxia-inducible factor 1alpha and CLOCK in transcriptional activation of the vasopressin gene. Mol. Cell. Neurosci. 2003. 22(3): 396. DOI: https://doi.org/10.1016/s1044-7431(02)00019-2
  65. Yu C., Yang S.L., Fang X., Jiang J.X., Sun C.Y., Huang T. Hypoxia disrupts the expression levels of circadian rhythm genes in hepatocellular carcinoma. Mol. Med. Rep. 2015. 11(5): 4002. DOI: https://doi.org/10.3892/mmr.2015.3199
  66. Koyanagi S., Kuramoto Y., Nakagawa H., Aramaki H., Ohdo S., Soeda S., Shimeno H. A molecular mechanism regulating circadian expression of vascular endothelial growth factor in tumor cells. Cancer Res. 2003. 63(21): 7277.
  67. Wu Y., Tang D., Liu N., Xiong W., Huang H., Li Y., Ma Z., Zhao H., Chen P., Qi X., Zhang E.E. Reciprocal regulation between the circadian clock and hypoxia signaling at the genome level in mammals. Cell Metab. 2017. 25(1): 73. DOI: https://doi.org/10.1016/j.cmet.2016.09.009
  68. Merck to Acquire Peloton Therapeutics, Bolstering Oncology Pipeline. https://www.businesswire.com/news/home/20190521005432/en/Merck-Acquire-Peloton-Therapeutics-Bolstering-Oncology-Pipeline