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Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes

Nature Medicine volume 7, pages 437–443 (2001)Cite this article

Abstract

Low oxygen tension influences tumor progression by enhancing angiogenesis; and histone deacetylases (HDAC) are implicated in alteration of chromatin assembly and tumorigenesis. Here we show induction of HDAC under hypoxia and elucidate a role for HDAC in the regulation of hypoxia-induced angiogenesis. Overexpressed wild-type HDAC1 downregulated expression of p53 and von Hippel–Lindau tumor suppressor genes and stimulated angiogenesis of human endothelial cells. A specific HDAC inhibitor, trichostatin A (TSA), upregulated p53 and von Hippel–Lindau expression and downregulated hypoxia-inducible factor-1α and vascular endothelial growth factor. TSA also blocked angiogenesis in vitro and in vivo. TSA specifically inhibited hypoxia-induced angiogenesis in the Lewis lung carcinoma model. These results indicate that hypoxia enhances HDAC function and that HDAC is closely involved in angiogenesis through suppression of hypoxia-responsive tumor suppressor genes.

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Figure 1: Activity and expression of HDAC are regulated by oxygen tension.
Figure 2: Effect of TSA on the regulation of p53, VHL, HIF-1α and VEGF expression.
Figure 3: Anti-angiogenic activity of TSA.
Figure 4: Regulation of hypoxia-responsible genes by HDAC overexpression.
Figure 5: Angiogenic stimulation of wt-HDAC1 overexpression.
Figure 6: Induction of HDAC in hypoxic tumor regions and inhibition of hypoxia-induced angiogenesis by TSA in Lewis lung carcinoma model.

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References

  1. Grunstein, M. Histone acetylation in chromatin structure and transcription. Nature 389, 349–352 (1997).

    Article  CAS  Google Scholar 

  2. Laherty, C.D. et al. Histone deacetylases associated with the mSin3 corepressor mediate Mad transcriptional repression. Cell 89, 349–356 (1997).

    Article  CAS  Google Scholar 

  3. Nagy, L. et al. Nuclear receptor repression mediated by a complex containing SMRT, mSin3A and histone deacetylase. Cell 89, 373–380 (1997).

    Article  CAS  Google Scholar 

  4. Kosugi, H. et al. Histone deacetylase inhibitors are the potent inducer/enhancer of differentiation in acute myeloid leukemia: a new approach to anti-leukemia therapy. Leukemia 13, 1316–1324 (1999).

    Article  CAS  Google Scholar 

  5. Kouzarides, T. Histone acetylases and deacetylases in cell proliferation. Curr. Opin. Genet. Dev. 9, 40–48 (1999).

    Article  CAS  Google Scholar 

  6. Guillemin, K. & Krasnow, M.A. The hypoxic response: huffing and HIFing. Cell 89, 9–12 (1997).

    Article  CAS  Google Scholar 

  7. Ryan, H.E., Lo, J. & Johnson, R.S. HIF-1α is required for solid tumor formation and embryonic vascularization. EMBO J. 17, 3005–3015 (1998).

    Article  CAS  Google Scholar 

  8. Kim, K.W. et al. Insulin-like growth factor II induced by hypoxia may contribute to angiogenesis of human hepatocellular carcinoma. Cancer Res. 58, 348–351 (1998).

    CAS  Google Scholar 

  9. Carmeliet, P. et al. Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394, 485–490 (1998).

    Article  CAS  Google Scholar 

  10. Nor, J.E., Christensen, J., Mooney, D.J. & Polverini, P.J. Vascular endothelial growth factor (VEGF)-mediated angiogenesis is associated with enhanced endothelial cell survival and induction of Bcl-2 expression. Am. J. Pathol. 154, 375–384 (1999).

    Article  CAS  Google Scholar 

  11. Gupta, K. et al. VEGF prevents apoptosis of human microvascular endothelial cells via opposing effects on MAPK/ERK and SAPK/JNK signaling. Exp. Cell Res. 247, 495–504 (1999).

    Article  CAS  Google Scholar 

  12. Baek, J.H. et al. Hypoxia-induced VEGF enhances tumor survivability via suppression of serum deprivation-induced apoptosis. Oncogene 19, 4621–4631 (2000).

    Article  CAS  Google Scholar 

  13. Gerber, H.P., Condorelli, F., Park, J. & Ferrara, N. Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. Flt-1, but not Flk-1/KDR, is upregulated by hypoxia. J. Biol. Chem. 272, 23659–23667 (1997).

    Article  CAS  Google Scholar 

  14. Waltenberger, J., Mayr, U., Pentz, S. & Hombach, V. Functional upregulation of the vascular endothelial growth factor receptor KDR by hypoxia. Circulation 94, 1647–1654 (1996).

    Article  CAS  Google Scholar 

  15. Kwon, H.J., Owa, T., Hassig, C.A., Shimada, J. & Schreiber, S.L. Depudecin induces morphological reversion of transformed fibroblasts via the inhibition of histone deacetylase. Proc. Natl. Acad. Sci. USA 95, 3356–3361 (1998).

    Article  CAS  Google Scholar 

  16. Ravi, R. et al. Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1α. Genes Dev. 14, 34–44 (2000).

    CAS  PubMed Central  Google Scholar 

  17. Stratmann, R., Krieg, M., Haas, R. & Plate, K.H. Putative control of angiogenesis in hemangioblastomas by the von Hippel-Lindau tumor suppressor gene. J. Neuropathol. Exp. Neurol. 56, 1242–1252 (1997).

    Article  CAS  Google Scholar 

  18. Pal, S., Claffey, K.P., Dvorak, H.F. & Mukhopadhyay, D. The von Hippel-Lindau gene product inhibits vascular permeability factor/vascular endothelial growth factor expression in renal cell carcinoma by blocking protein kinase C pathways. J. Biol. Chem. 272, 27509–27512 (1997).

    Article  CAS  Google Scholar 

  19. Royds, J.A., Dower, S.K., Qwarnstrom, E.E. & Lewis, C.E. Response of tumour cells to hypoxia: role of p53 and NF-κB. Mol. Pathol. 51, 55–61 (1998).

    Article  CAS  Google Scholar 

  20. Gnarra, J.R. et al. Post-transcriptional regulation of vascular endothelial growth factor mRNA by the product of the VHL tumor suppressor gene. Proc. Natl. Acad. Sci. USA 93, 10589–10594 (1996).

    Article  CAS  Google Scholar 

  21. Schmaltz, C., Hardenbergh, P.H., Wells, A. & Fisher, D.E. Regulation of proliferation-survival decisions during tumor cell hypoxia. Mol. Cell. Biol. 18, 2845–2854 (1998).

    Article  CAS  Google Scholar 

  22. Long, X. et al. p53 and the hypoxia-induced apoptosis of cultured neonatal rat cardiac myocytes. J. Clin. Invest. 99, 2635–2643 (1997).

    Article  CAS  Google Scholar 

  23. Blagosklonny, M.V. et al. p53 inhibits hypoxia-inducible factor-stimulated transcription. J. Biol. Chem. 273, 11995–11998 (1998).

    Article  CAS  Google Scholar 

  24. Krieg, M. et al. Up-regulation of hypoxia-inducible factors HIF-1α and HIF-2α under normoxic conditions in renal carcinoma cells by von Hoppel-Lindau tumor suppressor gene loss of function. Oncogene 19, 5435–5443 (2000).

    Article  CAS  Google Scholar 

  25. Mukhopadhyay, D., Tsiokas, L. & Sukhatme, V.P. Wild-type p53 and v-Src exert opposing influences on human vascular endothelial growth factor gene expression. Cancer Res. 55, 6161–6165 (1995).

    CAS  Google Scholar 

  26. Mukhopadhyay, D., Knebelmann, B., Cohen, H.T., Ananth, S. & Sukhatme, V.P. The von Hippel-Lindau tumor suppressor gene product interacts with Sp1 to repress vascular endothelial growth factor promoter activity. Mol. Cell. Biol. 17, 5629–5639 (1997).

    Article  CAS  Google Scholar 

  27. Krieg, M., Marti, H.H. & Plate, K.H. Coexpression of erythropoietin and vascular endothelial growth factor in nervous system tumors associated with von Hippel-Lindau tumor suppressor gene loss of function. Blood 92, 3388–3393 (1998).

    CAS  Google Scholar 

  28. Zhong, H. et al. Overexpression of hypoxia-inducible factor 1α in common human cancers and their metastases. Cancer Res. 59, 5830–5835 (1999).

    CAS  Google Scholar 

  29. Varia, M.A. et al. Pimonidazole: A novel hypoxia marker for complementary study of tumor hypoxia and cell proliferation in cervical carcinoma. Gynecol. Oncol. 71, 270–277 (1998).

    Article  CAS  Google Scholar 

  30. Meininger, C.J., Schelling, M.E. & Granger, H.J. Adenosine and hypoxia stimulate proliferation and migration of endothelial cells. Am. J. Physiol. 255, H554–H562 (1988).

    CAS  Google Scholar 

  31. Conrad, K.P. & Benyo, D.F. Placental cytokines and the pathogenesis of preeclampsia. Am. J. Reprod. Immunol. 37, 240–249 (1997).

    Article  CAS  Google Scholar 

  32. Hassig, C.A. et al. A role for histone deacetylase activity in HDAC1-mediated transcriptional repression. Proc. Natl. Acad. Sci. USA 95, 3519–3524 (1998).

    Article  CAS  Google Scholar 

  33. Dangond, F. & Gullans, S.R. Differential expression of human histone deacetylase mRNAs in response to immune cell apoptosis induction by trichostatin A and butyrate. Biochem. Biophys. Res. Commun. 247, 833–837 (1998).

    Article  CAS  Google Scholar 

  34. Bartl, S. et al. Identification of mouse histone deacetylase 1 as a growth factor-inducible gene. Mol. Cell. Biol. 17, 5033–5043 (1997).

    Article  CAS  Google Scholar 

  35. Nan, X. et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393, 386–389 (1998).

    Article  CAS  Google Scholar 

  36. Schroeder, M. & Mass, M.J. CpG methylation inactivates the transcriptional activity of the promoter of the human p53 tumor suppressor gene. Biochem. Biophys. Res. Commun. 235, 403–406 (1997).

    Article  CAS  Google Scholar 

  37. Prowse, A.H. et al. Somatic inactivation of the VHL gene in Von Hippel-Lindau disease tumors. Am. J. Hum. Genet. 60, 765–771 (1997).

    CAS  PubMed Central  Google Scholar 

  38. Herman, J.G. et al. Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc. Natl. Acad. Sci. USA 91, 9700–9704 (1994).

    Article  CAS  Google Scholar 

  39. Cameron, E.E., Bachman, K.E., Myohanen, S., Herman, J.G. & Baylin, S.B. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nature Genet. 21,103–107 (1999).

    Article  CAS  Google Scholar 

  40. Selker, E.U. Trichostatin A causes selective loss of DNA methylation in Neurospora. Proc. Natl. Acad. Sci. USA 95, 9430–9435 (1998).

    Article  CAS  Google Scholar 

  41. Morwenna, S. & Ratcliffe, W.P. Mammalian oxygen sensing and hypoxia inducible factor-1. Int. J. Biochem. Cell Biol. 29, 1419–1432 (1997).

    Article  CAS  Google Scholar 

  42. Kim, M.S. et al. Anti-angiogenic and Anti-invasive Activity of Torilin, a Sesquiterpene isolated from Torilis japonica. Int. J. Cancer 87, 269–275 (2000).

    Article  CAS  Google Scholar 

  43. Yamamoto, H., Itoh, F., Hinoda, Y. & Imai, K. Inverse association of cell adhesion regulator messenger RNA expression with metastasis in human colorectal cancer. Cancer Res. 56, 3605–3609 (1996).

    CAS  Google Scholar 

  44. Passaniti, A. et al. A simple, quantitative method for assessing angiogenesis and antiangiogenic agents using reconstituted basement membrane, heparin, and fibroblast growth factor. Lab. Invest. 67, 519–528 (1992).

    CAS  Google Scholar 

  45. Lee, Y.M. et al. Determination of hypoxic region by hypoxia marker in developing mouse embryos in vivo: A possible signal for vessel development. Dev. Dyn. 220, 175–186 (2001).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank S.L. Schreiber for the gift of pBJ5-wt-HDAC1–expressing vector; J.A. Raleigh for hypoxia marker, pimonidazole and its associated antibody; and B.P. Yu for critical reading of the manuscript. Financial support was from the National Research Laboratory Fund (2000-N-NL-01-C-015), the Ministry of Science and Technology, Korea (to K-W.K.) and the Korea Science and Engineering Foundation (to H.J.K.).

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Authors and Affiliations

  1. Department of Molecular Biology, Pusan National University, Pusan, Korea

    Myoung Sook Kim, You Mie Lee, Jin Hyen Baek, Jae-Eun Jang, Sae-Won Lee, Eun-Joung Moon, Hae-Sun Kim & Seok-Ki Lee

  2. Department of Pharmacy, Pusan National University, Pusan, Korea

    Hae Young Chung

  3. Department of Bioscience and Biotechnology, Sejong University, Seoul, Korea

    Ho Jeong Kwon

  4. Department of Pathology, College of Medicine, Seoul National University, Seoul, Korea

    Chul Woo Kim

  5. Angiogenesis Research Laboratory, College of Pharmacy, Seoul National University, Seoul, Korea

    Kyu-Won Kim

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Kim, M., Kwon, H., Lee, Y. et al. Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nat Med 7, 437–443 (2001). https://doi.org/10.1038/86507

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