DOI QR코드

DOI QR Code

Suppression of HIF-1α by Valproic Acid Sustains Self-Renewal of Mouse Embryonic Stem Cells under Hypoxia In Vitro

  • Lee, Hyo-Jong (College of Pharmacy, Inje University) ;
  • Kim, Kyu-Won (Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University)
  • Received : 2012.03.06
  • Accepted : 2012.04.10
  • Published : 2012.05.31

Abstract

The developing embryo naturally experiences relatively low oxygen conditions in vivo. Under in vitro hypoxia, mouse embryonic stem cells (mESCs) lose their self-renewal activity and display an early differentiated morphology mediated by the hypoxia-inducible factor-$1{\alpha}$ (HIF-$1{\alpha}$). Previously, we demonstrated that histone deacetylase (HDAC) is activated by hypoxia and increases the protein stability and transcriptional activity of HIF-$1{\alpha}$ in many human cancer cells. Furthermore HDAC1 and 3 mediate the differentiation of mECSs and hematopoietic stem cells. However, the role of HDACs and their inhibitors in hypoxia-induced early differentiation of mESCs remains largely unknown. Here, we examined the effects of several histone deacetylase inhibitors (HDACIs) on the self-renewal properties of mESCs under hypoxia. Inhibition of HDAC under hypoxia effectively decreased the HIF-$1{\alpha}$ protein levels and substantially improved the expression of the LIF-specific receptor (LIFR) and phosphorylated-STAT3 in mESCs. In particular, valproic acid (VPA), a pan HDACI, showed dramatic changes in HIF-$1{\alpha}$ protein levels and LIFR protein expression levels compared to other HDACIs, including sodium butyrate (SB), trichostatin A (TSA), and apicidin (AP). Importantly, our RT-PCR data and alkaline phosphatase assays indicate that VPA helps to maintain the self-renewal activity of mESCs under hypoxia. Taken together, these results suggest that VPA may block the early differentiation of mESCs under hypoxia via the destabilization of HIF-$1{\alpha}$.

Keywords

References

  1. Balasubramaniyan, V., Boddeke, E., Bakels, R., Küst, B., Kooistra, S., Veneman, A. and Copray, S. (2006) Effects of histone deacetylation inhibition on neuronal differentiation of embryonic mouse neural stem cells. Neuroscience 143, 939-951. https://doi.org/10.1016/j.neuroscience.2006.08.082
  2. Bartova, E., Galiova, G., Krejci, J., Harnicarova, A., Strasak, L. and Kozubek, S. (2008) Epigenome and chromatin structure in human embryonic stem cells undergoing differentiation. Dev. Dyn. 237, 3690-3702. https://doi.org/10.1002/dvdy.21773
  3. Bae, S. H., Jeong, J. W., Park, J. A., Kim, S. H., Bea, M. K, Choi, S. J. and Kim, K. W. (2004) Sumoylation increases HIF-1 alpha stability and its transcriptional activity. Biochem. Biophys. Res. Commun. 324, 394-400. https://doi.org/10.1016/j.bbrc.2004.09.068
  4. Berra, E., Benizri, E., Ginouvès, A., Volmat, V., Roux, D. and Pouyssegur, J. (2003) HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia. EMBO J. 22, 4082-4090. https://doi.org/10.1093/emboj/cdg392
  5. Blanchard, F., Kinzie, E., Wang, Y., Duplomb, L., Godard, A., Held, W. A., Asch, B. B. and Baumann, H. (2002) FR901228, an inhibitor of histone deacetylases, increases the cellular responsiveness to IL-6 type cytokines by enhancing the expression of receptor proteins. Oncogene 21, 6264-6277. https://doi.org/10.1038/sj.onc.1205777
  6. Bost, F., Caron, L., Marchetti, I., Dani, C., Le Marchand-Brustel, Y. and Binétruy, B. (2002) Retinoic acid activation of the ERK pathway is required for embryonic stem cell commitment into the adipocyte lineage. Biochem. J. 361, 621-627. https://doi.org/10.1042/0264-6021:3610621
  7. Du, K. L., Chen, M., Li, J., Lepore, J. J., Mericko, P. and Parmacek, M. S. (2004) Megakaryoblastic leukemia factor-1 transduces cytoskeletal signals and induces smooth muscle cell differentiation from undifferentiated embryonic stem cells. J. Biol. Chem. 279, 17578-17586. https://doi.org/10.1074/jbc.M400961200
  8. Efroni, S., Duttagupta, R., Cheng, J., Dehghani, H., Hoeppner, D. J., Dash, C., Bazett-Jones, D. P., Le Grice, S., McKay, R. D., Buetow, K. H., Gingeras, T. R., Misteli, T. and Meshorer, E. (2008) Global transcription in pluripotent embryonic stem cells. Cell Stem Cell 2, 437-447. https://doi.org/10.1016/j.stem.2008.03.021
  9. Ernst, M., Novak, U., Nicholson, S. E., Layton, J. E. and Dunn, A. R. (1999) The carboxyl-terminal domains of gp130-related cytokine receptors are necessary for suppressing embryonic stem cell differentiation. Involvement of STAT3. J. Biol. Chem. 274, 9729-9737. https://doi.org/10.1074/jbc.274.14.9729
  10. Evans, M. J. and Kaufman, M. H. (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292, 154-156. https://doi.org/10.1038/292154a0
  11. Gassmann, M., Fandrey, J., Bichet, S., Wartenberg, M., Marti, H. H., Bauer, C., Wenger, R. H. and Acker, H. (1996) Oxygen supply and oxygen-dependent gene expression in differentiating embryonic stem cells. Proc. Natl. Acad. Sci. USA 93, 2867-2872. https://doi.org/10.1073/pnas.93.7.2867
  12. Huangfu, D., Maehr, R., Guo, W., Eijkelenboom, A., Snitow, M., Chen, A. E. and Melton, D. A. (2008a) Induction of pluripotent stem cells by defi ned factors is greatly improved by small-molecule compounds. Nat. Biotechnol. 26, 795-797. https://doi.org/10.1038/nbt1418
  13. Huangfu, D., Osafune, K., Maehr, R., Guo, W., Eijkelenboom, A., Chen, S., Muhlestein, W. and Melton, D. A. (2008b) Induction of pluripotent stem cells from primary human fi broblasts with only Oct4 and Sox2. Nat. Biotechnol. 26, 1269-1275. https://doi.org/10.1038/nbt.1502
  14. Intaglietta, M., Johnson, P. C. and Winslow, R. M. (1996) Microvascular and tissue oxygen distribution. Cardiovasc. Res. 32, 632-643. https://doi.org/10.1016/0008-6363(96)00110-1
  15. Jeong, C. H., Lee, H. J., Cha, J. H., Kim, J. H., Kim, K. R., Kim, J. H., Yoon, D. K. and Kim, K. W. (2007) Hypoxia-inducible factor-1 alpha inhibits self-renewal of mouse embryonic stem cells in Vitro via negative regulation of the leukemia inhibitory factor-STAT3 pathway. J. Biol. Chem. 282, 13672-13679. https://doi.org/10.1074/jbc.M700534200
  16. Jeong, J. W., Bae, M. K., Ahn, M. Y., Kim, S. H., Sohn, T. K., Bae, M. H., Yoo, M. A., Song, E. J., Lee, K. J. and Kim, K. W. (2002) Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation. Cell 111, 709-720. https://doi.org/10.1016/S0092-8674(02)01085-1
  17. Karamboulas, C., Swedani, A., Ward, C., Al-Madhoun, A. S., Wilton, S., Boisvenue, S., Ridgeway, A. G. and Skerjanc, I. S. (2006) HDAC activity regulates entry of mesoderm cells into the cardiac muscle lineage. J. Cell Sci. 119, 4305-4314. https://doi.org/10.1242/jcs.03185
  18. Kim, M. J., Moon, C. H., Kim, M. Y., Kim, M. H., Lee, S. H., Baik, E. J. and Jung, Y. S. (2004) Role of PKC-delta during hypoxia in heartderived H9c2 cells. Jpn. J. Physiol. 54, 405-414. https://doi.org/10.2170/jjphysiol.54.405
  19. Kim, S. H., Jeong, J. W., Park, J. A., Lee, J. W., Seo, J. H., Jung, B. K., Bae, M. K. and Kim, K. W. (2007) Regulation of the HIF-1alpha stability by histone deacetylases. Oncol. Rep. 17, 647-651.
  20. Krejci, J., Uhlirova, R., Galiova, G., Kozubek, S., Smigova, J. and Bartova, E. (2009) Genome-wide reduction in H3K9 acetylation during human embryonic stem cell differentiation. J. Cell Physiol. 219, 677-687. https://doi.org/10.1002/jcp.21714
  21. Land, S. C. (2004) Hochachka's "Hypoxia Defense Strategies" and the development of the pathway for oxygen. Comp. Biochem. Physiol. B. Biochem. Mol. Biol. 139, 415-433. https://doi.org/10.1016/j.cbpc.2004.02.016
  22. Lee, H. J., Jeong, C. H., Cha, J. H. and Kim, K. W. (2010) PKC-delta inhibitors sustain self-renewal of mouse embryonic stem cells under hypoxia in vitro. Exp. Mol. Med. 42, 294-301. https://doi.org/10.3858/emm.2010.42.4.028
  23. Lee, J. W., Bae, S. H., Jeong, J. W., Kim, S. H. and Kim, K. W. (2004) Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions. Exp. Mol. Med. 36, 1-12. https://doi.org/10.1038/emm.2004.1
  24. Lee, J. W., Park, J. A., Kim, S. H., Seo, J. H., Lim, K. J., Jeong, J. W., Jeong, C. H., Chun, K. H., Lee, S. K., Kwon, Y. G. and Kim, K. W. (2007) Protein kinase C-delta regulates the stability of hypoxiainducible factor-1 alpha under hypoxia. Cancer Sci. 98, 1476-1481. https://doi.org/10.1111/j.1349-7006.2007.00535.x
  25. Lee, Y. M., Jeong, C. H., Koo, S. Y., Son, M. J., Song, H. S., Bae, S. K., Raleigh, J. A., Chung, H. Y., Yoo, M. A. and Kim, K. W. (2001) Determination of hypoxic region by hypoxia marker in developing mouse embryos in vivo: a possible signal for vessel development. Dev. Dyn. 220, 175-186. https://doi.org/10.1002/1097-0177(20010201)220:2<175::AID-DVDY1101>3.0.CO;2-F
  26. Li, Z., Wu J. C., Sheikh, A. Y., Kraft, D., Cao, F., Xie, X., Patel, M., Gambhir, S. S., Robbins, R. C., Cooke, J. P. and Wu, J. C. (2007) Differentiation, survival, and function of embryonic stem cell derived endothelial cells for ischemic heart disease. Circulation 116, 146-154. https://doi.org/10.1161/CIRCULATIONAHA.107.702894
  27. Maltepe, E., Krampitz, G. W., Okazaki, K. M., Red-Horse, K., Mak, W., Simon, M. C. and Fisher, S. J. (2005) Hypoxia-inducible factordependent histone deacetylase activity determines stem cell fate in the placenta. Development 132, 3393-3403. https://doi.org/10.1242/dev.01923
  28. Masuda, S., Kobayashi, T., Chikuma, M., Nagao, M. and Sasaki, R. (2000) The oviduct produces erythropoietin in an estrogen- and oxygen-dependent manner. Am. J. Physiol. Endocrinol. Metab. 278, E1038-1044.
  29. Matsuda, T., Nakamura, T., Nakao, K., Arai, T., Katsuki, M., Heike, T. and Yokota, T. (1999) STAT3 activation is suffi cient to maintain an undifferentiated state of mouse embryonic stem cells. EMBO. J. 18, 4261-4269. https://doi.org/10.1093/emboj/18.15.4261
  30. McCool, K. W., Xu, X., Singer, D. B., Murdoch, F. E. and Fritsch, M. K. (2007) The role of histone acetylation in regulating early gene expression patterns during early embryonic stem cell differentiation. J. Biol. Chem. 282, 6696-6706.
  31. Niwa, H., Burdon, T., Chambers, I. and Smith, A. (1998) Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. Genes. Dev. 12, 2048-2060. https://doi.org/10.1101/gad.12.13.2048
  32. Peyssonnaux, C., Zinkernagel, A. S., Schuepbach, R. A., Rankin, E., Vaulont, S., Haase, V. H., Nizet, V. and Johnson, R. S. (2007) Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J. Clin. Invest. 117, 1926-1932. https://doi.org/10.1172/JCI31370
  33. Powers, D. E., Millman, J. R., Huang, R. B. and Colton, C. K. (2008) Effects of oxygen on mouse embryonic stem cell growth, phenotype retention, and cellular energetics. Biotechnol. Bioeng. 101, 241-254. https://doi.org/10.1002/bit.21986
  34. Schrenk-Siemens, K., Perez-Alcala, S., Richter, J., Lacroix, E., Rahuel, J., Korte, M., Muller, U., Barde, Y. A. and Bibel, M. (2008) Embryonic stem cell-derived neurons as a cellular system to study gene function: lack of amyloid precursor proteins APP and APLP2 leads to defective synaptic transmission. Stem Cells 26, 2153-2163. https://doi.org/10.1634/stemcells.2008-0010
  35. Semenza, G. L. (2001) HIF-1, O(2), and the 3 PHDs: how animal cells signal hypoxia to the nucleus. Cell 107, 1-3. https://doi.org/10.1016/S0092-8674(01)00518-9
  36. Shui, Y. B., Fu, J. J., Garcia, C., Dattilo, L. K., Rajagopal, R., McMillan, S., Mak, G., Holekamp, N. M., Lewis, A. and Beebe, D. C. (2006) Oxygen distribution in the rabbit eye and oxygen consumption by the lens. Invest. Ophthalmol. Vis. Sci. 47, 1571-1580. https://doi.org/10.1167/iovs.05-1475
  37. Simon, M. C. and Keith, B. (2008) The role of oxygen availability in embryonic development and stem cell function. Nat. Rev. Mol. Cell Biol. 9, 285-296. https://doi.org/10.1038/nrm2354
  38. Tighe, A. P. and Gudas, L. J. (2004) Retinoic acid inhibits leukemia inhibitory factor signaling pathways in mouse embryonic stem cells. J. Cell Physiol. 198, 223-229. https://doi.org/10.1002/jcp.10424
  39. Yu, J. and Thomson, J. A. (2008) Pluripotent stem cell lines. Genes Dev. 22, 1987-1997. https://doi.org/10.1101/gad.1689808

Cited by

  1. The stabilization of hypoxia inducible factor modulates differentiation status and inhibits the proliferation of mouse embryonic stem cells vol.244, 2016, https://doi.org/10.1016/j.cbi.2015.12.007
  2. The Differential Effects of 2% Oxygen Preconditioning on the Subsequent Differentiation of Mouse and Human Pluripotent Stem Cells vol.23, pp.16, 2014, https://doi.org/10.1089/scd.2013.0504
  3. Effect of Hypoxia on the Differentiation and the Self-Renewal of Metanephrogenic Mesenchymal Stem Cells vol.2017, 2017, https://doi.org/10.1155/2017/7168687
  4. Impact of Oxygen Levels on Human Hematopoietic Stem and Progenitor Cell Expansion vol.25, pp.20, 2016, https://doi.org/10.1089/scd.2016.0153
  5. Induction of LIFR confers a dormancy phenotype in breast cancer cells disseminated to the bone marrow vol.18, pp.10, 2016, https://doi.org/10.1038/ncb3408
  6. Overexpression of ERβ is sufficient to inhibit hypoxia-inducible factor-1 transactivation vol.450, pp.1, 2014, https://doi.org/10.1016/j.bbrc.2014.05.107