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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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AURKB, in concert with REST, acts as an oxygen-sensitive epigenetic regulator of the hypoxic induction of MDM2

  • Kim, Iljin (Department of Pharmacology, Inha University College of Medicine) ;
  • Choi, Sanga (Department of Pharmacology, Inha University College of Medicine) ;
  • Yoo, Seongkyeong (Department of Pharmacology, Inha University College of Medicine) ;
  • Lee, Mingyu (Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School) ;
  • Park, Jong-Wan (Department of Pharmacology, Seoul National University College of Medicine)
  • Received : 2022.01.26
  • Accepted : 2022.04.08
  • Published : 2022.06.30
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Abstract

The acute response to hypoxia is mainly driven by hypoxia-inducible factors, but their effects gradually subside with time. Hypoxia-specific histone modifications may be important for the stable maintenance of long-term adaptation to hypoxia. However, little is known about the molecular mechanisms underlying the dynamic alterations of histones under hypoxic conditions. We found that the phosphorylation of histone H3 at Ser-10 (H3S10) was noticeably attenuated after hypoxic challenge, which was mediated by the inhibition of aurora kinase B (AURKB). To understand the role of AURKB in epigenetic regulation, DNA microarray and transcription factor binding site analyses combined with proteomics analysis were performed. Under normoxia, phosphorylated AURKB, in concert with the repressor element-1 silencing transcription factor (REST), phosphorylates H3S10, which allows the AURKB-REST complex to access the MDM2 proto-oncogene. REST then acts as a transcriptional repressor of MDM2 and downregulates its expression. Under hypoxia, AURKB is dephosphorylated and the AURKB-REST complex fails to access MDM2, leading to the upregulation of its expression. In this study, we present a case of hypoxia-specific epigenetic regulation of the oxygen-sensitive AURKB signaling pathway. To better understand the cellular adaptation to hypoxia, it is worthwhile to further investigate the epigenetic regulation of genes under hypoxic conditions.

Keywords

Acknowledgement

This study was supported by the National Research Foundation of Korea (2019R1A2B5B03069677, 2020R1A4A2002903, and 2021R1C1C2004561).

References

  1. Kaelin WG Jr and Ratcliffe PJ (2008) Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell 30, 393-402 https://doi.org/10.1016/j.molcel.2008.04.009
  2. Bartoszewski R, Moszynska A, Serocki M et al (2019) Primary endothelial cell-specific regulation of hypoxia-inducible factor (HIF)-1 and HIF-2 and their target gene expression profiles during hypoxia. FASEB J 33, 7929-7941 https://doi.org/10.1096/fj.201802650rr
  3. Ginouves A, Ilc K, Macias N, Pouyssegur J and Berra E (2008) PHDs overactivation during chronic hypoxia "desensitizes" HIF alpha and protects cells from necrosis. Proc Natl Acad Sci U S A 105, 4745-4750 https://doi.org/10.1073/pnas.0705680105
  4. Kang J, Shin SH, Yoon H et al (2018) FIH is an oxygen sensor in ovarian cancer for G9a/GLP-driven epigenetic regulation of metastasis-related genes. Cancer Res 78, 1184-1199 https://doi.org/10.1158/0008-5472.CAN-17-2506
  5. Chakraborty AA, Laukka T, Myllykoski M et al (2019) Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate. Science 363, 1217 https://doi.org/10.1126/science.aaw1026
  6. Perez-Cadahia B, Drobic B and Davie JR (2009) H3 phosphorylation: dual role in mitosis and interphase. Biochem Cell Biol 87, 695-709 https://doi.org/10.1139/o09-053
  7. Baek SH (2011) When signaling kinases meet histones and histone modifiers in the nucleus. Mol Cell 42, 274-284 https://doi.org/10.1016/j.molcel.2011.03.022
  8. Willems E, Dedobbeleer M, Digregorio M, Lombard A, Lumapat PN and Rogister B (2018) The functional diversity of Aurora kinases: a comprehensive review. Cell Div 13, 7 https://doi.org/10.1186/s13008-018-0040-6
  9. Ooi L and Wood IC (2007) Chromatin crosstalk in development and disease: lessons from REST. Nat Rev Genet 8, 544-554 https://doi.org/10.1038/nrg2100
  10. Cavadas MAS, Mesnieres M, Crifo B et al (2016) REST is a hypoxia-responsive transcriptional repressor. Sci Rep 6, 31355 https://doi.org/10.1038/srep31355
  11. Hwang JY and Zukin RS (2018) REST, a master transcriptional regulator in neurodegenerative disease. Curr Opin Neurol 48, 193-200 https://doi.org/10.1016/j.conb.2017.12.008
  12. Cheong A, Bingham AJ, Li J et al (2005) Downregulated REST transcription factor is a switch enabling critical potassium channel expression and cell proliferation. Mol Cell 20, 45-52 https://doi.org/10.1016/j.molcel.2005.08.030
  13. Kuwahara K, Saito Y, Ogawa E et al (2001) The neuron-restrictive silencer element-neuron-restrictive silencer factor system regulates basal and endothelin 1-inducible atrial natriuretic peptide gene expression in ventricular myocytes. Mol Cell Biol 21, 2085-2097 https://doi.org/10.1128/MCB.21.6.2085-2097.2001
  14. Negrini S, Prada I, D'Alessandro R and Meldolesi J (2013) REST: an oncogene or a tumor suppressor? Trends Cell Biol 23, 289-295 https://doi.org/10.1016/j.tcb.2013.01.006
  15. Barrett TD, Palomino HL, Brondstetter TI et al (2011) Pharmacological characterization of 1-(5-chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (JNJ42041935), a potent and selective hypoxia-inducible factor prolyl hydroxylase inhibitor. Mol Pharmacol 79, 910-920 https://doi.org/10.1124/mol.110.070508
  16. Chan MC, Ilott NE, Schodel J et al (2016) Tuning the transcriptional response to hypoxia by inhibiting hypoxiainducible factor (HIF) prolyl and asparaginyl hydroxylases. J Biol Chem 291, 20661-20673 https://doi.org/10.1074/jbc.M116.749291
  17. Frost J, Galdeano C, Soares P et al (2016) Potent and selective chemical probe of hypoxic signalling downstream of HIF-alpha hydroxylation via VHL inhibition. Nat Commun 7, 13312 https://doi.org/10.1038/ncomms13312
  18. Lim D, Do Y, Kwon BS et al (2020) Angiogenesis and vasculogenic mimicry as therapeutic targets in ovarian cancer. BMB Rep 53, 291-298 https://doi.org/10.5483/BMBRep.2020.53.6.060
  19. Manfredi JJ (2010) The Mdm2-p53 relationship evolves: Mdm2 swings both ways as an oncogene and a tumor suppressor. Genes Dev 24, 1580-1589 https://doi.org/10.1101/gad.1941710
  20. Fischer M (2017) Census and evaluation of p53 target genes. Oncogene 36, 3943-3956 https://doi.org/10.1038/onc.2016.502
  21. Kim I and Park JW (2020) Hypoxia-driven epigenetic regulation in cancer progression: a focus on histone methylation and its modifying enzymes. Cancer Lett 489, 41-49 https://doi.org/10.1016/j.canlet.2020.05.025
  22. Batie M, Frost J, Frost M, Wilson JW, Schofield P and Rocha S (2019) Hypoxia induces rapid changes to histone methylation and reprograms chromatin. Science 363, 1222 https://doi.org/10.1126/science.aau5870
  23. Hwang S, Kim S, Kim K, Yeom J, Park S and Kim I (2020) Euchromatin histone methyltransferase II (EHMT2) regulates the expression of ras-related GTP binding C (RRAGC) protein. BMB Rep 53, 576-581 https://doi.org/10.5483/BMBRep.2020.53.11.055
  24. Komar D and Juszczynski P (2020) Rebelled epigenome: histone H3S10 phosphorylation and H3S10 kinases in cancer biology and therapy. Clin Epigenetics 12, 147 https://doi.org/10.1186/s13148-020-00941-2
  25. Nie M, Wang YD, Yu ZN et al (2020) AURKB promotes gastric cancer progression via activation of CCND1 expression. Aging (Albany NY) 12, 1304-1321 https://doi.org/10.18632/aging.102684
  26. Biswas K, Sarkar S, Said N, Brautigan DL and Larner JM (2020) Aurora B kinase promotes CHIP-dependent degradation of HIF1 alpha in prostate cancer cells. Mol Cancer Ther 19, 1008-1017 https://doi.org/10.1158/1535-7163.mct-19-0777
  27. Klein AM, de Queiroz RM, Venkatesh D and Prives C (2021) The roles and regulation of MDM2 and MDMX: it is not just about p53. Genes Dev 35, 575-601 https://doi.org/10.1101/gad.347872.120
  28. Fahraeus R and Olivares-Illana V (2014) MDM2's social network. Oncogene 33, 4365-4376 https://doi.org/10.1038/onc.2013.410
  29. Zhang L and Hill RP (2004) Hypoxia enhances metastatic efficiency by up-regulating Mdm2 in KHT cells and increasing resistance to apoptosis. Cancer Res 64, 4180-4189 https://doi.org/10.1158/0008-5472.CAN-03-3038
  30. Shaikh MF, Morano WF, Lee J et al (2016) Emerging role of mdm2 as target for anti-cancer therapy: a review. Ann Clin Lab Sci 46, 627-634
  31. Nieminen AL, Qanungo S, Schneider EA, Jiang BH and Agani FH (2005) Mdm2 and HIF-1alpha interaction in tumor cells during hypoxia. J Cell Physiol 204, 364-369 https://doi.org/10.1002/jcp.20406
  32. Joshi S, Singh AR and Durden DL (2014) MDM2 regulates hypoxic hypoxia-inducible factor 1alpha stability in an E3 ligase, proteasome, and PTEN-phosphatidylinositol 3-kinaseAKT-dependent manner. J Biol Chem 289, 22785-22797 https://doi.org/10.1074/jbc.M114.587493
  33. Ravi R, Mookerjee B, Bhujwalla ZM et al (2000) Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes Dev 14, 34-44 https://doi.org/10.1101/gad.14.1.34
  34. Kim HL, Yeo EJ, Chun YS and Park JW (2006) A domain responsible for HIF-1alpha degradation by YC-1, a novel anticancer agent. Int J Oncol 29, 255-260
  35. Kim I, Shin SH, Lee JE and Park JW (2019) Oxygen sensor FIH inhibits HACE1-dependent ubiquitination of Rac1 to enhance metastatic potential in breast cancer cells. Oncogene 38, 3651-3666 https://doi.org/10.1038/s41388-019-0676-y
  36. Chun YS, Choi E, Kim GT et al (2000) Zinc induces the accumulation of hypoxia-inducible factor (HIF)-1 alpha, but inhibits the nuclear translocation of HIF-1 beta, causing HIF-1 inactivation. Biochem Biophys Res Commun 268, 652-656 https://doi.org/10.1006/bbrc.2000.2180