Inhibition of lymphangiogenic factor VEGF-C expression and production by the histone deacetylase inhibitor suberoylanilide hydroxamic acid in breast cancer cells

Cheng,Hsueh-Tsen; Hung,Wen-Chun

doi:10.3892/or.2012.2188

Inhibition of lymphangiogenic factor VEGF-C expression and production by the histone deacetylase inhibitor suberoylanilide hydroxamic acid in breast cancer cells

Authors:
- Hsueh-Tsen Cheng
- Wen-Chun Hung
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Affiliations: Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan, R.O.C., National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan, R.O.C.
Published online on: December 14, 2012 https://doi.org/10.3892/or.2012.2188
Pages: 1238-1244

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Abstract

Suberoylanilide hydroxamic acid (SAHA), a potent histone deacetylase (HDAC) inhibitor, has been shown to exert anticancer effects in various types of human cancer and is now used in the clinic for cancer treatment. In addition to cytostatic and cytotoxic activities, SAHA also represses angiogenesis to inhibit tumor growth. However, the effect of SAHA on tumor lymphangiogenesis, a step in which cancer cells produce pro-lymphangiogenic factors such as vascular endothelial growth factor-C (VEGF-C) to stimulate proliferation and migration of lymphatic endothelial cells, remains largely unclear. In this study, we investigated the expression of VEGF-C in breast cancer cell lines and found that VEGF-C was highly expressed in MDA-MB-231, MCF-7, MDA-MB-453 and BT-474 cells. SAHA inhibited VEGF-C expression in a dose-dependent manner in these cell lines. The secretion of VEGF-C into conditioned medium was also suppressed. We cloned human VEGF-C gene promoter and demonstrated that SAHA directly repressed promoter activity in MDA-MB-231 cells. Promoter deletion assay suggested that SAHA repressed VEGF-C via the -185/+38 region which contained several transcription factor binding sites. Notably, we found that SAHA reduced Sp1, but not Sp3 and NF-κB protein levels. Treatment with Sp1 inhibitor mithramycin A also inhibited VEGF-C expression in breast cancer cells. In addition, enforced expression of Sp1 partially rescued the inhibition of VEGF-C by SAHA. Collectively, our results suggest that SAHA inhibits VEGF-C expression in breast cancer cells via transcriptional repression and this drug may exert anti-lymphangiogenic activity in cancer treatment.

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1	Sarkies P and Sale JE: Cellular epigenetic stability and cancer. Trends Genet. 28:118–127. 2012. View Article : Google Scholar : PubMed/NCBI
2	Esteller M and Herman JG: Cancer as an epigenetic disease: DNA methylation and chromatin alterations in human tumours. J Pathol. 196:1–7. 2002. View Article : Google Scholar : PubMed/NCBI
3	Kouzarides T: Chromatin modifications and their function. Cell. 128:693–705. 2007. View Article : Google Scholar : PubMed/NCBI
4	Huang L and Pardee AB: Suberoylanilide hydroxamic acid as a potential therapeutic agent for human breast cancer treatment. Mol Med. 6:849–866. 2000.PubMed/NCBI
5	Kim MS, Kwon HJ, Lee YM, et al: Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nat Med. 7:437–443. 2001. View Article : Google Scholar : PubMed/NCBI
6	Butler LM, Agus DB, Scher HI, et al: Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo. Cancer Res. 60:5165–5170. 2000.PubMed/NCBI
7	Marks P, Rifkind RA, Richon VM, Breslow R, Miller T and Kelly WK: Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer. 1:194–202. 2001. View Article : Google Scholar : PubMed/NCBI
8	Minucci S and Pelicci PG: Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer. 6:38–51. 2006. View Article : Google Scholar : PubMed/NCBI
9	Marks PA and Breslow R: Dimethyl sulfoxide to vorinostat: Development of this histone deacetylase inhibitor as an anticancer drug. Nat Biotechnol. 25:84–90. 2007. View Article : Google Scholar : PubMed/NCBI
10	Duvic M and Vu J: Vorinostat: a new oral histone deacetylase inhibitor approved for cutaneous T-cell lymphoma. Expert Opin Investig Drugs. 16:1111–1120. 2007. View Article : Google Scholar : PubMed/NCBI
11	Peart MJ, Tainton KM, Ruefli AA, et al: Novel mechanisms of apoptosis induced by histone deacetylase inhibitors. Cancer Res. 63:4460–4471. 2003.PubMed/NCBI
12	Shao Y, Gao Z, Marks PA and Jiang X: Apoptotic and autophagic cell death induced by histone deacetylase inhibitors. Proc Natl Acad Sci USA. 101:18030–18035. 2004. View Article : Google Scholar : PubMed/NCBI
13	Gui CY, Ngo L, Xu WS, Richon VM and Marks PA: Histone deacetylase (HDAC) inhibitor activation of p21^WAF1 involves changes in promoter-associated proteins, including HDAC1. Proc Natl Acad Sci USA. 101:1241–1246. 2004. View Article : Google Scholar : PubMed/NCBI
14	Mitsiades CS, Mitsiades NS, McMullan CJ, et al: Transcriptional signature of histone deacetylase inhibition in multiple myeloma: Biological and clinical implications. Proc Natl Acad Sci USA. 101:540–545. 2004. View Article : Google Scholar : PubMed/NCBI
15	Khan AN and Tomasi TB: Histone deacetylase regulation of immune gene expression in tumor cells. Immunol Res. 40:164–178. 2008. View Article : Google Scholar : PubMed/NCBI
16	Ogbomo H, Michaelis M, Kreuter J, Doerr HW and Cinatl J Jr: Histone deacetylase inhibitors suppress natural killer cell cytolytic activity. FEBS Lett. 581:1317–1322. 2007. View Article : Google Scholar : PubMed/NCBI
17	Deroanne CF, Bonjean K, Servotte S, et al: Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling. Oncogene. 21:427–436. 2002. View Article : Google Scholar : PubMed/NCBI
18	Alitalo K, Tammela T and Petrova TV: Lymphangiogenesis in development and human disease. Nature. 438:946–953. 2005. View Article : Google Scholar : PubMed/NCBI
19	Mandriota SJ, Jussila L, Jeltsch M, et al: Vascular endothelial growth factor-C- mediated lymphangiogenesis promotes tumour metastasis. EMBO J. 20:672–682. 2001. View Article : Google Scholar : PubMed/NCBI
20	Maula SM, Luukkaa M, Grenman R, Jackson D, Jalkanen S and Ristamaki R: Intratumoral lymphatics are essential for the metastatic spread and prognosis in squamous cell carcinomas of the head and neck region. Cancer Res. 63:1920–1926. 2003.
21	Dadras SS, Paul T, Bertoncini J, et al: Tumor lymphangiogenesis: a novel prognostic indaicator for cutaneous melanoma metastasis and survival. Am J Pathol. 162:1951–1960. 2003. View Article : Google Scholar : PubMed/NCBI
22	Valtola R, Salven P, Heikkila P, et al: VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer. Am J Pathol. 154:1381–1390. 1999. View Article : Google Scholar : PubMed/NCBI
23	Wang CA, Jedlicka P, Patrick AN, et al: Six1 induces lymphangiogenesis and metastasis via upregulation of VEGF-C in mouse models of breast cancer. J Clin Invest. 122:1895–1906. 2012. View Article : Google Scholar : PubMed/NCBI
24	Skobe M, Hawighorst T, Jackson DG, et al: Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med. 7:192–198. 2001. View Article : Google Scholar : PubMed/NCBI
25	Flaherty KT: Sorafenib in renal cell carcinoma. Clin Cancer Res. 13:S747–S752. 2007. View Article : Google Scholar
26	Hanrahan EO and Heymach JV: Vascular endothelial growth factor receptor tyrosine kinase inhibitors Vandetanib (ZD6474) and AZD2171 in lung cancer. Clin Cancer Res. 13:S4617–S4622. 2007. View Article : Google Scholar : PubMed/NCBI
27	Jimenez X, Lu D, Brennan L, et al: A recombinant, fully human, bispecific antibody neutralizes the biological activities mediated by both vascular endothelial growth factor receptors 2 and 3. Mol Cancer Ther. 4:427–434. 2005.
28	Roberts N, Kloos B, Cassella M, et al: Inhibition of VEGFR-3 activation with the antagonistic antibody more potently suppresses lymph node and distant metastases than inactivation of VEGFR-2. Cancer Res. 66:2650–2657. 2006. View Article : Google Scholar : PubMed/NCBI
29	McDonald DM: New antibody to stop tumor angiogenesis and lymphatic spread by blocking receptor partnering. Cancer Cell. 18:541–543. 2010. View Article : Google Scholar : PubMed/NCBI
30	Rinderknecht M, Villa A, Ballmer-Hofer K, Neri D and Detmar M: Phage-derived fully human monoclonal antibody fragments to human vascular endothelial growth factor-C block its interaction with VEGF receptor-2 and 3. PLoS One. 5:e119412010. View Article : Google Scholar
31	Chilov D, Kukk E, Taira S, et al: Genomic organization of human and mouse genes for vascular endothelial growth factor C. J Biol Chem. 272:25176–25183. 1997. View Article : Google Scholar : PubMed/NCBI
32	Li L and Davie JR: The role of Sp1 and Sp3 in normal and cancer cell biology. Ann Anat. 192:275–283. 2010. View Article : Google Scholar : PubMed/NCBI
33	Wang L, Wei D, Huang S, et al: Transcription factor Sp1 expression is a significant predictor of survival in human gastric cancer. Clin Cancer Res. 9:6371–6380. 2003.PubMed/NCBI
34	Safe S and Abdelrahim M: Sp transcription factor family and its role in cancer. Eur J Cancer. 41:2438–2448. 2005. View Article : Google Scholar : PubMed/NCBI
35	Hung JJ, Wang YT and Chang WC: Sp1 deacetylation induced by phorbol ester recruits p300 to activate 12(S)-lipoxygenase gene transcription. Mol Cell Biol. 26:1770–1785. 2006. View Article : Google Scholar : PubMed/NCBI
36	Wang SA, Chuang JY, Yeh SH, et al: Heat shock protein 90 is important for Sp1 stability during mitosis. J Mol Biol. 387:1106–1119. 2009. View Article : Google Scholar : PubMed/NCBI
37	Li D, Marchenko ND and Moll UM: SAHA shows preferential cytotoxicity in mutant p53 cancer cells by destabilizing mutant p53 through inhibition of the HDAC6- Hsp90 chaperone axis. Cell Death Differ. 19:1268–1276. 2012.PubMed/NCBI