Skip to main content
Log in

Histone deacetylase inhibitors such as sodium butyrate and trichostatin A inhibit vascular endothelial growth factor (VEGF) secretion from human glioblastoma cells

  • Original Article
  • Published:
Brain Tumor Pathology Aims and scope Submit manuscript

Abstract

We investigated the effects of histone deacetylase (HDAC) inhibitors such as sodium butyrate (SB) and trichostatin A (TSA) on the expression of vascular endothelial growth factor (VEGF) by human glioblastoma T98G, U251MG, and U87MG cells. The glioblastoma cells secreted three VEGF isoforms, VEGF (189), (165), and (121), although the expression levels of VEGF differed between the cell types. Treatment with either 5mM SB or 100ng/ml TSA reduced VEGF secretion in conditioned media and reduced VEGF mRNA expression. We also studied the expression of VEGF-B,-C, and-D mRNA in human glioblastoma cells and their modulation by HDAC inhibitors. The PCR products of VEGF-B (357 bp), VEGF-C (501 bp), and VEGF-D (484 bp) were amplified in all glioblastoma cells examined. Treatment with SB reduced the expression of VEGF-D mRNA in U251MG cells and the expression of VEGF-B mRNA in U87MG cells. TSA treatment reduced the expression of VEGF-D in U251MG cells. These results suggest that HDAC inhibitors reduce VEGF secretion and modulate the expression of the other VEGF family members, and therefore may inhibit angiogenesis in glioblastoma tissues.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Potorak Z, Cohen T, Sivan R, et al (1997) VEGF 145, a secreted vascular endothelial growth factor isoform that binds to extracellular matrix. J Biol Chem 272:7151–7158

    Article  Google Scholar 

  2. Maglione D, Guerriero V, Viglietto G, et al (1991) Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc Natl Acad Sci USA 88:9267–9271

    Article  PubMed  CAS  Google Scholar 

  3. Olofsson B, Pajusola K, Kaipainen A, et al (1996) Vascular endothelial growth factor B, a novel growth factor for endothelial cells. Proc Natl Acad Sci USA 93:2576–2581

    Article  PubMed  CAS  Google Scholar 

  4. Kaipainen A, Korhonen J, Mustonen T, et al (1995) Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc Natl Acad Sci USA 92: 3566–3570

    Article  PubMed  CAS  Google Scholar 

  5. Achen MG, Jeltsch M, Kukk E, et al (1998) Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinase VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proc Natl Acad Sci USA 95:548–553

    Article  PubMed  CAS  Google Scholar 

  6. Ito N, Sawa H, Nagane M, et al (2001) Inhibitory effects of sodium butyrate on proliferation and invasiveness of human glioma cells. Neurosurgery 49:430–437

    Article  PubMed  CAS  Google Scholar 

  7. Sawa H, Murakami H, Ohshima Y, et al (2001) Histone deacetylase inhibitors such as sodium butyrate and trichostatin A induce apoptosis through an increase of the bcl-2-related protein Bad. Brain Tumor Pathol 18:109–114

    Article  PubMed  CAS  Google Scholar 

  8. Cheng SY, Huang HJ, Nagane M, et al (1996) Suppression of glioblastoma angiogenicity and tumorigenicity by inhibition of endogenous expression of vascular endothelial growth factor. Proc Natl Acad Sci USA 93:8502–8507

    Article  PubMed  CAS  Google Scholar 

  9. Yu JL, Rak JW, Klement G, et al (2002) Vascular endothelial growth factor isoform expression as a determinant of blood vessel patterning in human melanoma xenografts. Cancer Res 62:1838–1846.

    PubMed  CAS  Google Scholar 

  10. Cheng SY, Nagane M, Huang HS, et al (1997) Intracerebral tumor-associated hemorrhage caused by overexpression of the vascular endothelial growth factor isoforms VEGF 121 and VEGF 165 but not VEGF 189. Proc Natl Acad Sci USA 94:12081–12087

    Article  PubMed  CAS  Google Scholar 

  11. Malinen T, Jussila L, Veikkola T, et al (2001) Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nat Med 7:199–205

    Article  Google Scholar 

  12. Ueda M, Terai Y, Yamashita Y, et al (2002) Correlation between vascular endothelial growth factor-C expression and invasion phenotype in cervical carcinomas. Int J Cancer 98:335–343

    Article  PubMed  CAS  Google Scholar 

  13. Skobe M, Hawighorst T, Jackson DG, et al (2001) Induction of tumor lymphangiogenesis by VEGF-C promotes breast carcinoma metastasis. Nat Med 7:192–198

    Article  PubMed  CAS  Google Scholar 

  14. Kim MS, Kwon HJ, Lee YM, et al (2001) Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nat Med 7:437–443

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hiroki Sawa.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sawa, H., Murakami, H., Ohshima, Y. et al. Histone deacetylase inhibitors such as sodium butyrate and trichostatin A inhibit vascular endothelial growth factor (VEGF) secretion from human glioblastoma cells. Brain Tumor Pathol 19, 77–81 (2002). https://doi.org/10.1007/BF02478931

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02478931

Key words

Navigation