Skip to main content
SpringerLink
Log in

Epigenetic regulators: multifunctional proteins modulating hypoxia-inducible factor-α protein stability and activity

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

The hypoxia-inducible factor (HIF) is a heterodimeric transcription factor governing a transcriptional program in response to reduced O2 availability in metazoans. It contributes to physiology and pathogenesis of many human diseases through its downstream target genes. Emerging studies have shown that the transcriptional activity of HIF is highly regulated at multiple levels and the epigenetic regulators are essential for HIF-mediated transactivation. In this review, we will discuss the comprehensive regulation of HIF transcriptional activity by different types of epigenetic regulators.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Wang GL, Jiang BH, Rue EA, Semenza GL (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 92(12):5510–5514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Semenza GL, Wang GL (1992) 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 12(12):5447–5454

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Tian H, McKnight SL, Russell DW (1997) Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev 11(1):72–82

    Article  CAS  PubMed  Google Scholar 

  4. Gu YZ, Moran SM, Hogenesch JB, Wartman L, Bradfield CA (1998) Molecular characterization and chromosomal localization of a third alpha-class hypoxia inducible factor subunit, HIF3alpha. Gene Expr 7(3):205–213

    CAS  PubMed  Google Scholar 

  5. Keith B, Adelman DM, Simon MC (2001) Targeted mutation of the murine aryl hydrocarbon receptor nuclear translocator 2 (Arnt2) gene reveals partial redundancy with Arnt. Proc Natl Acad Sci USA 98(12):6692–6697. doi:10.1073/pnas.121494298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zhang P, Yao Q, Lu L, Li Y, Chen PJ, Duan C (2014) Hypoxia-inducible factor 3 is an oxygen-dependent transcription activator and regulates a distinct transcriptional response to hypoxia. Cell Rep 6(6):1110–1121. doi:10.1016/j.celrep.2014.02.011

    Article  CAS  PubMed  Google Scholar 

  7. Maynard MA, Evans AJ, Shi W, Kim WY, Liu FF, Ohh M (2007) Dominant-negative HIF-3 alpha 4 suppresses VHL-null renal cell carcinoma progression. Cell Cycle 6(22):2810–2816. doi:10.4161/cc.6.22.4947

    Article  CAS  PubMed  Google Scholar 

  8. Hirose K, Morita M, Ema M, Mimura J, Hamada H, Fujii H, Saijo Y, Gotoh O, Sogawa K, Fujii-Kuriyama Y (1996) 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(4):1706–1713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Drutel G, Kathmann M, Heron A, Schwartz JC, Arrang JM (1996) Cloning and selective expression in brain and kidney of ARNT2 homologous to the Ah receptor nuclear translocator (ARNT). Biochem Biophys Res Commun 225(2):333–339. doi:10.1006/bbrc.1996.1176

    Article  CAS  PubMed  Google Scholar 

  10. Semenza GL (2012) Hypoxia-inducible factors in physiology and medicine. Cell 148(3):399–408. doi:10.1016/j.cell.2012.01.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Huang Y, Kapere Ochieng J, Kempen MB, Munck AB, Swagemakers S, van Ijcken W, Grosveld F, Tibboel D, Rottier RJ (2013) Hypoxia inducible factor 3alpha plays a critical role in alveolarization and distal epithelial cell differentiation during mouse lung development. PLoS One 8(2):e57695. doi:10.1371/journal.pone.0057695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kobayashi S, Yamashita T, Ohneda K, Nagano M, Kimura K, Nakai H, Poellinger L, Ohneda O (2015) Hypoxia-inducible factor-3alpha promotes angiogenic activity of pulmonary endothelial cells by repressing the expression of the VE-cadherin gene. Genes Cells 20(3):224–241. doi:10.1111/gtc.12215

    Article  CAS  PubMed  Google Scholar 

  13. Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG Jr (2001) HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292(5516):464–468. doi:10.1126/science.1059817

    Article  CAS  PubMed  Google Scholar 

  14. Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ (1999) The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399(6733):271–275. doi:10.1038/20459

    Article  CAS  PubMed  Google Scholar 

  15. Semenza GL, Jiang BH, Leung SW, Passantino R, Concordet JP, Maire P, Giallongo A (1996) Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J Biol Chem 271(51):32529–32537

    Article  CAS  PubMed  Google Scholar 

  16. Arany Z, Huang LE, Eckner R, Bhattacharya S, Jiang C, Goldberg MA, Bunn HF, Livingston DM (1996) An essential role for p300/CBP in the cellular response to hypoxia. Proc Natl Acad Sci USA 93(23):12969–12973

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kasper LH, Boussouar F, Boyd K, Xu W, Biesen M, Rehg J, Baudino TA, Cleveland JL, Brindle PK (2005) Two transactivation mechanisms cooperate for the bulk of HIF-1-responsive gene expression. EMBO J 24(22):3846–3858. doi:10.1038/sj.emboj.7600846

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lando D, Peet DJ, Gorman JJ, Whelan DA, Whitelaw ML, Bruick RK (2002) FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev 16(12):1466–1471. doi:10.1101/gad.991402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Mahon PC, Hirota K, Semenza GL (2001) FIH-1: a novel protein that interacts with HIF-1α and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev 15(20):2675–2686. doi:10.1101/gad.924501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yasinska IM, Sumbayev VV (2003) S-nitrosation of Cys-800 of HIF-1alpha protein activates its interaction with p300 and stimulates its transcriptional activity. FEBS Lett 549(1–3):105–109. doi:10.1016/S0014-5793(03)00807-X

    Article  CAS  PubMed  Google Scholar 

  21. Luo W, Hu H, Chang R, Zhong J, Knabel M, O’Meally R, Cole RN, Pandey A, Semenza GL (2011) Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 145(5):732–744. doi:10.1016/j.cell.2011.03.054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chen Z, Liu X, Mei Z, Wang Z, Xiao W (2014) EAF2 suppresses hypoxia-induced factor 1alpha transcriptional activity by disrupting its interaction with coactivator CBP/p300. Mol Cell Biol 34(6):1085–1099. doi:10.1128/MCB.00718-13

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Hubbi ME, Gilkes DM, Baek JH, Semenza GL (2012) Four-and-a-half LIM domain proteins inhibit transactivation by hypoxia-inducible factor 1. J Biol Chem 287(9):6139–6149. doi:10.1074/jbc.M111.278630

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bhattacharya S, Michels CL, Leung MK, Arany ZP, Kung AL, Livingston DM (1999) Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1. Genes Dev 13(1):64–75

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Datta K, Li J, Bhattacharya R, Gasparian L, Wang E, Mukhopadhyay D (2004) Protein kinase C zeta transactivates hypoxia-inducible factor alpha by promoting its association with p300 in renal cancer. Cancer Res 64(2):456–462. doi:10.1158/0008-5472.CAN-03-2706

    Article  CAS  PubMed  Google Scholar 

  26. Emerling BM, Weinberg F, Liu JL, Mak TW, Chandel NS (2008) PTEN regulates p300-dependent hypoxia-inducible factor 1 transcriptional activity through Forkhead transcription factor 3a (FOXO3a). Proc Natl Acad Sci USA 105(7):2622–2627. doi:10.1073/pnas.0706790105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Moin SM, Chandra V, Arya R, Jameel S (2009) The hepatitis E virus ORF3 protein stabilizes HIF-1alpha and enhances HIF-1-mediated transcriptional activity through p300/CBP. Cell Microbiol 11(9):1409–1421. doi:10.1111/j.1462-5822.2009.01340.x

    Article  CAS  PubMed  Google Scholar 

  28. Mendonca DB, Mendonca G, Aragao FJ, Cooper LF (2011) NF-kappaB suppresses HIF-1alpha response by competing for P300 binding. Biochem Biophys Res Commun 404(4):997–1003. doi:10.1016/j.bbrc.2010.12.098

    Article  CAS  PubMed  Google Scholar 

  29. Seo HW, Kim EJ, Na H, Lee MO (2009) Transcriptional activation of hypoxia-inducible factor-1alpha by HDAC4 and HDAC5 involves differential recruitment of p300 and FIH-1. FEBS Lett 583(1):55–60. doi:10.1016/j.febslet.2008.11.044

    Article  CAS  PubMed  Google Scholar 

  30. Perez-Perri JI, Dengler VL, Audetat KA, Pandey A, Bonner EA, Urh M, Mendez J, Daniels DL, Wappner P, Galbraith MD, Espinosa JM (2016) The TIP60 complex is a conserved coactivator of HIF1A. Cell Rep 16(1):37–47. doi:10.1016/j.celrep.2016.05.082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kimura A, Horikoshi M (1998) Tip60 acetylates six lysines of a specific class in core histones in vitro. Genes Cells 3(12):789–800. doi:10.1016/j.celrep.2016.05.082

    Article  CAS  PubMed  Google Scholar 

  32. Geng H, Liu Q, Xue C, David LL, Beer TM, Thomas GV, Dai MS, Qian DZ (2012) HIF1alpha protein stability is increased by acetylation at lysine 709. J Biol Chem 287(42):35496–35505. doi:10.1074/jbc.M112.400697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Xenaki G, Ontikatze T, Rajendran R, Stratford IJ, Dive C, Krstic-Demonacos M, Demonacos C (2008) PCAF is an HIF-1alpha cofactor that regulates p53 transcriptional activity in hypoxia. Oncogene 27(44):5785–5796. doi:10.1038/onc.2008.192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lim JH, Lee YM, Chun YS, Chen J, Kim JE, Park JW (2010) Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. Mol Cell 38(6):864–878. doi:10.1016/j.molcel.2010.05.023

    Article  CAS  PubMed  Google Scholar 

  35. Jeong JW, Bae MK, Ahn MY, Kim SH, Sohn TK, Bae MH, Yoo MA, Song EJ, Lee KJ, Kim KW (2002) Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation. Cell 111(5):709–720. doi:10.1016/S0092-8674(02)01085-1

    Article  CAS  PubMed  Google Scholar 

  36. Murray-Rust TA, Oldham NJ, Hewitson KS, Schofield CJ (2006) Purified recombinant hARD1 does not catalyse acetylation of Lys532 of HIF-1alpha fragments in vitro. FEBS Lett 580(8):1911–1918. doi:10.1016/j.febslet.2006.02.012

    Article  CAS  PubMed  Google Scholar 

  37. Arnesen T, Kong X, Evjenth R, Gromyko D, Varhaug JE, Lin Z, Sang N, Caro J, Lillehaug JR (2005) Interaction between HIF-1 alpha (ODD) and hARD1 does not induce acetylation and destabilization of HIF-1 alpha. FEBS Lett 579(28):6428–6432. doi:10.1016/j.febslet.2005.10.036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lee JY, Park JH, Choi HJ, Won HY, Joo HS, Shin DH, Park MK, Han B, Kim KP, Lee TJ, Croce CM, Kong G (2017) LSD1 demethylates HIF1alpha to inhibit hydroxylation and ubiquitin-mediated degradation in tumor angiogenesis. Oncogene. doi:10.1038/onc.2017.158

    Google Scholar 

  39. Oh SY, Seok JY, Choi YS, Lee SH, Bae JS, Lee YM (2015) The histone methyltransferase inhibitor BIX01294 inhibits HIF-1alpha stability and angiogenesis. Mol Cells 38(6):528–534. doi:10.14348/molcells.2015.0026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ueda J, Ho JC, Lee KL, Kitajima S, Yang H, Sun W, Fukuhara N, Zaiden N, Chan SL, Tachibana M, Shinkai Y, Kato H, Poellinger L (2014) The hypoxia-inducible epigenetic regulators Jmjd1a and G9a provide a mechanistic link between angiogenesis and tumor growth. Mol Cell Biol 34(19):3702–3720. doi:10.1128/MCB.00099-14

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Casciello F, Al-Ejeh F, Kelly G, Brennan DJ, Ngiow SF, Young A, Stoll T, Windloch K, Hill MM, Smyth MJ, Gannon F, Lee JS (2017) G9a drives hypoxia-mediated gene repression for breast cancer cell survival and tumorigenesis. Proc Natl Acad Sci USA 114(27):7077–7082. doi:10.1073/pnas.1618706114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Chen H, Yan Y, Davidson TL, Shinkai Y, Costa M (2006) Hypoxic stress induces dimethylated histone H3 lysine 9 through histone methyltransferase G9a in mammalian cells. Cancer Res 66(18):9009–9016. doi:10.1158/0008-5472.CAN-06-0101

    Article  CAS  PubMed  Google Scholar 

  43. Lee JS, Kim Y, Kim IS, Kim B, Choi HJ, Lee JM, Shin HJ, Kim JH, Kim JY, Seo SB, Lee H, Binda O, Gozani O, Semenza GL, Kim M, Kim KI, Hwang D, Baek SH (2010) Negative regulation of hypoxic responses via induced Reptin methylation. Mol Cell 39(1):71–85. doi:10.1016/j.molcel.2010.06.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Liu Q, Geng H, Xue C, Beer TM (1853) Qian DZ (2015) Functional regulation of hypoxia inducible factor-1alpha by SET9 lysine methyltransferase. Biochim Biophys Acta 5:881–891. doi:10.1016/j.bbamcr.2015.01.011

    Google Scholar 

  45. Liu X, Chen Z, Xu C, Leng X, Cao H, Ouyang G, Xiao W (2015) Repression of hypoxia-inducible factor alpha signaling by Set7-mediated methylation. Nucleic Acids Res 43(10):5081–5098. doi:10.1093/nar/gkv379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kim Y, Nam HJ, Lee J, Park DY, Kim C, Yu YS, Kim D, Park SW, Bhin J, Hwang D, Lee H, Koh GY, Baek SH (2016) Methylation-dependent regulation of HIF-1alpha stability restricts retinal and tumour angiogenesis. Nat Commun 7:10347. doi:10.1038/ncomms10347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lafleur VN, Richard S, Richard DE (2014) Transcriptional repression of hypoxia-inducible factor-1 (HIF-1) by the protein arginine methyltransferase PRMT1. Mol Biol Cell 25(6):925–935. doi:10.1091/mbc.E13-07-0423

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Minet E, Ernest I, Michel G, Roland I, Remacle J, Raes M, Michiels C (1999) HIF1A gene transcription is dependent on a core promoter sequence encompassing activating and inhibiting sequences located upstream from the transcription initiation site and cis elements located within the 5′UTR. Biochem Biophys Res Commun 261(2):534–540. doi:10.1006/bbrc.1999.0995

    Article  CAS  PubMed  Google Scholar 

  49. Ju UI, Park JW, Park HS, Kim SJ, Chun YS (2015) FBXO11 represses cellular response to hypoxia by destabilizing hypoxia-inducible factor-1alpha mRNA. Biochem Biophys Res Commun 464(4):1008–1015. doi:10.1016/j.bbrc.2015.07.037

    Article  CAS  PubMed  Google Scholar 

  50. Lim JH, Choi YJ, Cho CH, Park JW (2012) Protein arginine methyltransferase 5 is an essential component of the hypoxia-inducible factor 1 signaling pathway. Biochem Biophys Res Commun 418(2):254–259. doi:10.1016/j.bbrc.2012.01.006

    Article  CAS  PubMed  Google Scholar 

  51. Mistry IN, Smith PJ, Wilson DI, Tavassoli A (2015) Probing the epigenetic regulation of HIF-1alpha transcription in developing tissue. Mol BioSyst 11(10):2780–2785. doi:10.1039/c5mb00281h

    Article  CAS  PubMed  Google Scholar 

  52. Koslowski M, Luxemburger U, Tureci O, Sahin U (2011) Tumor-associated CpG demethylation augments hypoxia-induced effects by positive autoregulation of HIF-1alpha. Oncogene 30(7):876–882. doi:10.1038/onc.2010.481

    Article  CAS  PubMed  Google Scholar 

  53. Pierre CC, Longo J, Bassey-Archibong BI, Hallett RM, Milosavljevic S, Beatty L, Hassell JA, Daniel JM (2015) Methylation-dependent regulation of hypoxia inducible factor-1 alpha gene expression by the transcription factor Kaiso. Biochim Biophys Acta 1849 12:1432–1441. doi:10.1016/j.bbagrm.2015.10.018

    Article  CAS  Google Scholar 

  54. Lachance G, Uniacke J, Audas TE, Holterman CE, Franovic A, Payette J, Lee S (2014) DNMT3a epigenetic program regulates the HIF-2alpha oxygen-sensing pathway and the cellular response to hypoxia. Proc Natl Acad Sci USA 111(21):7783–7788. doi:10.1073/pnas.1322909111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Pfeiffer S, Kruger J, Maierhofer A, Bottcher Y, Kloting N, El Hajj N, Schleinitz D, Schon MR, Dietrich A, Fasshauer M, Lohmann T, Dressler M, Stumvoll M, Haaf T, Bluher M, Kovacs P (2016) Hypoxia-inducible factor 3A gene expression and methylation in adipose tissue is related to adipose tissue dysfunction. Sci Rep 6:27969. doi:10.1038/srep27969

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Qian DZ, Kachhap SK, Collis SJ, Verheul HM, Carducci MA, Atadja P, Pili R (2006) Class II histone deacetylases are associated with VHL-independent regulation of hypoxia-inducible factor 1 alpha. Cancer Res 66(17):8814–8821. doi:10.1158/0008-5472.CAN-05-4598

    Article  CAS  PubMed  Google Scholar 

  57. Chang CC, Lin BR, Chen ST, Hsieh TH, Li YJ, Kuo MY (2011) HDAC2 promotes cell migration/invasion abilities through HIF-1alpha stabilization in human oral squamous cell carcinoma. J Oral Pathol Med 40(7):567–575. doi:10.1111/j.1600-0714.2011.01009.x

    Article  CAS  PubMed  Google Scholar 

  58. Geng H, Harvey CT, Pittsenbarger J, Liu Q, Beer TM, Xue C, Qian DZ (2011) HDAC4 protein regulates HIF1alpha protein lysine acetylation and cancer cell response to hypoxia. J Biol Chem 286(44):38095–38102. doi:10.1074/jbc.M111.257055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kim SH, Jeong JW, Park JA, Lee JW, Seo JH, Jung BK, Bae MK, Kim KW (2007) Regulation of the HIF-1alpha stability by histone deacetylases. Oncol Rep 17(3):647–651. doi:10.3892/or.17.3.647

    CAS  PubMed  Google Scholar 

  60. Kato H, Tamamizu-Kato S, Shibasaki F (2004) Histone deacetylase 7 associates with hypoxia-inducible factor 1alpha and increases transcriptional activity. J Biol Chem 279(40):41966–41974. doi:10.1074/jbc.M406320200

    Article  CAS  PubMed  Google Scholar 

  61. Imai S, Armstrong CM, Kaeberlein M, Guarente L (2000) Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403(6771):795–800. doi:10.1038/35001622

    Article  CAS  PubMed  Google Scholar 

  62. Blander G, Guarente L (2004) The Sir2 family of protein deacetylases. Annu Rev Biochem 73:417–435. doi:10.1146/annurev.biochem.73.011303.073651

    Article  CAS  PubMed  Google Scholar 

  63. Joo HY, Yun M, Jeong J, Park ER, Shin HJ, Woo SR, Jung JK, Kim YM, Park JJ, Kim J, Lee KH (2015) SIRT1 deacetylates and stabilizes hypoxia-inducible factor-1alpha (HIF-1alpha) via direct interactions during hypoxia. Biochem Biophys Res Commun 462(4):294–300. doi:10.1016/j.bbrc.2015.04.119

    Article  CAS  PubMed  Google Scholar 

  64. Laemmle A, Lechleiter A, Roh V, Schwarz C, Portmann S, Furer C, Keogh A, Tschan MP, Candinas D, Vorburger SA, Stroka D (2012) Inhibition of SIRT1 impairs the accumulation and transcriptional activity of HIF-1alpha protein under hypoxic conditions. PLoS One 7(3):e33433. doi:10.1371/journal.pone.0033433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Dioum EM, Chen R, Alexander MS, Zhang Q, Hogg RT, Gerard RD, Garcia JA (2009) Regulation of hypoxia-inducible factor 2alpha signaling by the stress-responsive deacetylase sirtuin 1. Science 324(5932):1289–1293. doi:10.1126/science.1169956

    Article  CAS  PubMed  Google Scholar 

  66. Yoon H, Shin SH, Shin DH, Chun YS, Park JW (2014) Differential roles of Sirt1 in HIF-1alpha and HIF-2alpha mediated hypoxic responses. Biochem Biophys Res Commun 444(1):36–43. doi:10.1016/j.bbrc.2014.01.001

    Article  CAS  PubMed  Google Scholar 

  67. Bae JU, Lee SJ, Seo KW, Kim YH, Park SY, Bae SS, Kim CD (2013) SIRT1 attenuates neointima formation by inhibiting HIF-1alpha expression in neointimal lesion of a murine wire-injured femoral artery. Int J Cardiol 168(4):4393–4396. doi:10.1016/j.ijcard.2013.05.044

    Article  PubMed  Google Scholar 

  68. Dong SY, Guo YJ, Feng Y, Cui XX, Kuo SH, Liu T, Wu YC (2016) The epigenetic regulation of HIF-1alpha by SIRT1 in MPP(+) treated SH-SY5Y cells. Biochem Biophys Res Commun 470(2):453–459. doi:10.1016/j.bbrc.2016.01.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Seo KS, Park JH, Heo JY, Jing K, Han J, Min KN, Kim C, Koh GY, Lim K, Kang GY, Uee Lee J, Yim YH, Shong M, Kwak TH, Kweon GR (2015) SIRT2 regulates tumour hypoxia response by promoting HIF-1alpha hydroxylation. Oncogene 34(11):1354–1362. doi:10.1038/onc.2014.76

    Article  CAS  PubMed  Google Scholar 

  70. Hubbi ME, Hu H, Kshitiz Gilkes DM, Semenza GL (2013) Sirtuin-7 inhibits the activity of hypoxia-inducible factors. J Biol Chem 288(29):20768–20775. doi:10.1074/jbc.M113.476903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Zhong L, D’Urso A, Toiber D, Sebastian C, Henry RE, Vadysirisack DD, Guimaraes A, Marinelli B, Wikstrom JD, Nir T, Clish CB, Vaitheesvaran B, Iliopoulos O, Kurland I, Dor Y, Weissleder R, Shirihai OS, Ellisen LW, Espinosa JM, Mostoslavsky R (2010) The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell 140(2):280–293. doi:10.1016/j.cell.2009.12.041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Bell EL, Emerling BM, Ricoult SJ, Guarente L (2011) SirT3 suppresses hypoxia inducible factor 1alpha and tumor growth by inhibiting mitochondrial ROS production. Oncogene 30(26):2986–2996. doi:10.1038/onc.2011.37

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Kohl R, Zhou J, Brune B (2006) Reactive oxygen species attenuate nitric-oxide-mediated hypoxia-inducible factor-1alpha stabilization. Free Radic Biol Med 40(8):1430–1442. doi:10.1016/j.freeradbiomed.2005.12.012

    Article  PubMed  CAS  Google Scholar 

  74. Johansson C, Tumber A, Che K, Cain P, Nowak R, Gileadi C, Oppermann U (2014) The roles of Jumonji-type oxygenases in human disease. Epigenomics 6(1):89–120. doi:10.2217/epi.13.79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Whetstine JR, Nottke A, Lan F, Huarte M, Smolikov S, Chen Z, Spooner E, Li E, Zhang G, Colaiacovo M, Shi Y (2006) Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell 125(3):467–481

    Article  CAS  PubMed  Google Scholar 

  76. Cloos PA, Christensen J, Agger K, Maiolica A, Rappsilber J, Antal T, Hansen KH, Helin K (2006) The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3. Nature 442(7100):307–311

    Article  CAS  PubMed  Google Scholar 

  77. Ponnaluri VK, Vavilala DT, Putty S, Gutheil WG, Mukherji M (2009) Identification of non-histone substrates for JMJD2A-C histone demethylases. Biochem Biophys Res Commun 390(2):280–284. doi:10.1016/j.bbrc.2009.09.107

    Article  CAS  PubMed  Google Scholar 

  78. Luo W, Chang R, Zhong J, Pandey A, Semenza GL (2012) Histone demethylase JMJD2C is a coactivator for hypoxia-inducible factor 1 that is required for breast cancer progression. Proc Natl Acad Sci USA 109(49):E3367–E3376. doi:10.1073/pnas.1217394109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Pollard PJ, Loenarz C, Mole DR, McDonough MA, Gleadle JM, Schofield CJ, Ratcliffe PJ (2008) Regulation of Jumonji-domain-containing histone demethylases by hypoxia-inducible factor (HIF)-1α. Biochem J 416(3):387–394. doi:10.1042/BJ20081238

    Article  CAS  PubMed  Google Scholar 

  80. Mimura I, Nangaku M, Kanki Y, Tsutsumi S, Inoue T, Kohro T, Yamamoto S, Fujita T, Shimamura T, Suehiro J, Taguchi A, Kobayashi M, Tanimura K, Inagaki T, Tanaka T, Hamakubo T, Sakai J, Aburatani H, Kodama T, Wada Y (2012) Dynamic change of chromatin conformation in response to hypoxia enhances the expression of GLUT3 (SLC2A3) by cooperative interaction of hypoxia-inducible factor 1 and KDM3A. Mol Cell Biol 32(15):3018–3032. doi:10.1128/MCB.06643-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Krieg AJ, Rankin EB, Chan D, Razorenova O, Fernandez S, Giaccia AJ (2010) Regulation of the histone demethylase JMJD1A by hypoxia-inducible factor 1 alpha enhances hypoxic gene expression and tumor growth. Mol Cell Biol 30(1):344–353. doi:10.1128/MCB.00444-09

    Article  CAS  PubMed  Google Scholar 

  82. Yang SJ, Park YS, Cho JH, Moon B, An HJ, Lee JY, Xie Z, Wang Y, Pocalyko D, Lee DC, Sohn HA, Kang M, Kim JY, Kim E, Park KC, Kim JA, Yeom YI (2017) Regulation of hypoxia responses by flavin adenine dinucleotide-dependent modulation of HIF-1alpha protein stability. EMBO J 36(8):1011–1028. doi:10.15252/embj.201694408

    Article  CAS  PubMed  Google Scholar 

  83. Liu YV, Baek JH, Zhang H, Diez R, Cole RN, Semenza GL (2007) RACK1 competes with HSP90 for binding to HIF-1α and is required for O2-independent and HSP90 inhibitor-induced degradation of HIF-1α. Mol Cell 25(2):207–217. doi:10.1016/j.molcel.2007.01.001

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Shen L, Song CX, He C, Zhang Y (2014) Mechanism and function of oxidative reversal of DNA and RNA methylation. Annu Rev Biochem 83:585–614. doi:10.1146/annurev-biochem-060713-035513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, He C, Zhang Y (2011) Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333(6047):1300–1303. doi:10.1126/science.1210597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Tsai YP, Chen HF, Chen SY, Cheng WC, Wang HW, Shen ZJ, Song C, Teng SC, He C, Wu KJ (2014) TET1 regulates hypoxia-induced epithelial-mesenchymal transition by acting as a co-activator. Genome Biol 15(12):513. doi:10.1186/s13059-014-0513-0

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Wu MZ, Tsai YP, Yang MH, Huang CH, Chang SY, Chang CC, Teng SC, Wu KJ (2011) Interplay between HDAC3 and WDR5 is essential for hypoxia-induced epithelial-mesenchymal transition. Mol Cell 43(5):811–822. doi:10.1016/j.molcel.2011.07.012

    Article  CAS  PubMed  Google Scholar 

  88. Chang S, Park B, Choi K, Moon Y, Lee HY, Park H (2016) Hypoxic reprograming of H3K27me3 and H3K4me3 at the INK4A locus. FEBS Lett 590(19):3407–3415. doi:10.1002/1873-3468.12375

    Article  CAS  PubMed  Google Scholar 

  89. Zhou X, Sun H, Chen H, Zavadil J, Kluz T, Arita A, Costa M (2010) Hypoxia induces trimethylated H3 lysine 4 by inhibition of JARID1A demethylase. Cancer Res 70(10):4214–4221. doi:10.1158/0008-5472.CAN-09-2942

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Johnson AB, Denko N, Barton MC (2008) Hypoxia induces a novel signature of chromatin modifications and global repression of transcription. Mutat Res 640(1–2):174–179. doi:10.1016/j.mrfmmm.2008.01.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Dobrynin G, McAllister TE, Leszczynska KB, Ramachandran S, Krieg AJ, Kawamura A, Hammond EM (2017) KDM4A regulates HIF-1 levels through H3K9me3. Sci Rep 7(1):11094. doi:10.1038/s41598-017-11658-3

    Article  PubMed  PubMed Central  Google Scholar 

  92. Jang MK, Mochizuki K, Zhou M, Jeong HS, Brady JN, Ozato K (2005) The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Mol Cell 19(4):523–534. doi:10.1016/j.molcel.2005.06.027

    Article  CAS  PubMed  Google Scholar 

  93. Wu SY, Lee AY, Lai HT, Zhang H, Chiang CM (2013) Phospho switch triggers Brd4 chromatin binding and activator recruitment for gene-specific targeting. Mol Cell 49(5):843–857. doi:10.1016/j.molcel.2012.12.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Shi J, Wang Y, Zeng L, Wu Y, Deng J, Zhang Q, Lin Y, Li J, Kang T, Tao M, Rusinova E, Zhang G, Wang C, Zhu H, Yao J, Zeng YX, Evers BM, Zhou MM, Zhou BP (2014) Disrupting the interaction of BRD4 with diacetylated Twist suppresses tumorigenesis in basal-like breast cancer. Cancer Cell 25(2):210–225. doi:10.1016/j.ccr.2014.01.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. da Motta LL, Ledaki I, Purshouse K, Haider S, De Bastiani MA, Baban D, Morotti M, Steers G, Wigfield S, Bridges E, Li JL, Knapp S, Ebner D, Klamt F, Harris AL, McIntyre A (2017) The BET inhibitor JQ1 selectively impairs tumour response to hypoxia and downregulates CA9 and angiogenesis in triple negative breast cancer. Oncogene 36(1):122–132. doi:10.1038/onc.2016.184

    Article  PubMed  CAS  Google Scholar 

  96. Nair SS, Kumar R (2012) Chromatin remodeling in cancer: a gateway to regulate gene transcription. Mol Oncol 6(6):611–619. doi:10.1016/j.molonc.2012.09.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kirmes I, Szczurek A, Prakash K, Charapitsa I, Heiser C, Musheev M, Schock F, Fornalczyk K, Ma D, Birk U, Cremer C, Reid G (2015) A transient ischemic environment induces reversible compaction of chromatin. Genome Biol 16:246. doi:10.1186/s13059-015-0802-2

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Sena JA, Wang L, Hu CJ (2013) BRG1 and BRM chromatin-remodeling complexes regulate the hypoxia response by acting as coactivators for a subset of hypoxia-inducible transcription factor target genes. Mol Cell Biol 33(19):3849–3863. doi:10.1128/MCB.00731-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Wang F, Zhang R, Beischlag TV, Muchardt C, Yaniv M, Hankinson O (2004) Roles of Brahma and Brahma/SWI2-related gene 1 in hypoxic induction of the erythropoietin gene. J Biol Chem 279(45):46733–46741. doi:10.1074/jbc.M409002200

    Article  CAS  PubMed  Google Scholar 

  100. Wang F, Zhang R, Wu X, Hankinson O (2010) Roles of coactivators in hypoxic induction of the erythropoietin gene. PLoS One 5(4):e10002. doi:10.1371/journal.pone.0010002

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Kenneth NS, Mudie S, van Uden P, Rocha S (2009) SWI/SNF regulates the cellular response to hypoxia. J Biol Chem 284(7):4123–4131. doi:10.1074/jbc.M808491200

    Article  CAS  PubMed  Google Scholar 

  102. Melvin A, Mudie S, Rocha S (2011) The chromatin remodeler ISWI regulates the cellular response to hypoxia: role of FIH. Mol Biol Cell 22(21):4171–4181. doi:10.1091/mbc.E11-02-0163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Dayan F, Roux D, Brahimi-Horn MC, Pouyssegur J, Mazure NM (2006) The oxygen sensor factor-inhibiting hypoxia-inducible factor-1 controls expression of distinct genes through the bifunctional transcriptional character of hypoxia-inducible factor-1alpha. Cancer Res 66(7):3688–3698. doi:10.1158/0008-5472.CAN-05-4564

    Article  CAS  PubMed  Google Scholar 

  104. Huber O, Menard L, Haurie V, Nicou A, Taras D, Rosenbaum J (2008) Pontin and reptin, two related ATPases with multiple roles in cancer. Cancer Res 68(17):6873–6876. doi:10.1158/0008-5472.CAN-08-0547

    Article  CAS  PubMed  Google Scholar 

  105. Lee JS, Kim Y, Bhin J, Shin HJ, Nam HJ, Lee SH, Yoon JB, Binda O, Gozani O, Hwang D, Baek SH (2011) Hypoxia-induced methylation of a pontin chromatin remodeling factor. Proc Natl Acad Sci USA 108(33):13510–13515. doi:10.1073/pnas.1106106108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Yoo YG, Kong G, Lee MO (2006) Metastasis-associated protein 1 enhances stability of hypoxia-inducible factor-1alpha protein by recruiting histone deacetylase 1. EMBO J 25(6):1231–1241. doi:10.1038/sj.emboj.7601025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Moon HE, Cheon H, Chun KH, Lee SK, Kim YS, Jung BK, Park JA, Kim SH, Jeong JW, Lee MS (2006) Metastasis-associated protein 1 enhances angiogenesis by stabilization of HIF-1alpha. Oncol Rep 16(4):929–935. doi:10.3892/or.16.4.929

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Carole Baas for language proofreading. Work in authors’ laboratories was supported by Grants from NIH (R00CA168746), CPRIT (RR140036), Susan G. Komen® (CCR16376227), Welch Foundation (I-1903-20160319), and American Cancer Society and UTSW Simmons Cancer Center (ACS-IRG-02-196) to W.L.; and NIH (R00NS078049, R35GM124693), Welch Foundation (I-1939-20170325), CPRIT-HIHR RP170671, Darrell K Royal Research Fund, TIBIR pilot Grant, and UTSW startup funds to Y. W.. W. L. is a CPRIT Scholar in Cancer Research.

Author information

Authors and Affiliations

  1. Department of Pathology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA

    Weibo Luo & Yingfei Wang

  2. Department of Pharmacology, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA

    Weibo Luo

  3. Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA

    Yingfei Wang

Authors
  1. Weibo Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yingfei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Weibo Luo or Yingfei Wang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Luo, W., Wang, Y. Epigenetic regulators: multifunctional proteins modulating hypoxia-inducible factor-α protein stability and activity. Cell. Mol. Life Sci. 75, 1043–1056 (2018). https://doi.org/10.1007/s00018-017-2684-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-017-2684-9

Keywords

Search

Navigation