title: Inhibition of lymphangiogenic factor VEGF-C expression and production             by the histone deacetylase inhibitor suberoylanilide hydroxamic acid in breast             cancer cells.
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.
authors.affiliation: Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan, ROC.
authors.forename: Hsueh-Tsen
authors.initials: HT
authors.lastname: Cheng
authors.forename: Wen-Chun
authors.initials: WC
authors.lastname: Hung
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms; D015536:Down-Regulation; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D061986:MCF-7 Cells; D011401:Promoter Regions, Genetic; D016329:Sp1 Transcription Factor / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism*; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D016329:Sp1 Transcription Factor; C467486:VEGFC protein, human; D042582:Vascular Endothelial Growth Factor C; D000077337:Vorinostat