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Suberoylanilide hydroxamic acid (SAHA), a potent histone deacetylase (HDAC)inhibitor, has been shown to exert anticancer effects in various types of humancancer and is now used in the clinic for cancer treatment. In addition to cytostaticand cytotoxic activities, SAHA also represses angiogenesis to inhibit tumor growth.However, the effect of SAHA on tumor lymphangiogenesis, a step in which cancercells produce pro-lymphangiogenic factors such as vascular endothelial growthfactor-C (VEGF-C) to stimulate proliferation and migration of lymphatic endothelialcells, remains largely unclear. In this study, we investigated the expressionof VEGF-C in breast cancer cell lines and found that VEGF-C was highly expressedin MDA-MB-231, MCF-7, MDA-MB-453 and BT-474 cells. SAHA inhibited VEGF-C expressionin a dose-dependent manner in these cell lines. The secretion of VEGF-C into conditionedmedium was also suppressed. We cloned human VEGF-C gene promoter and demonstratedthat SAHA directly repressed promoter activity in MDA-MB-231 cells. Promoter deletionassay suggested that SAHA repressed VEGF-C via the -185/+38 region which containedseveral transcription factor binding sites. Notably, we found that SAHA reducedSp1, but not Sp3 and NF-κB protein levels. Treatment with Sp1 inhibitor mithramycin Aalso inhibited VEGF-C expression in breast cancer cells. In addition, enforcedexpression of Sp1 partially rescued the inhibition of VEGF-C by SAHA. Collectively,our results suggest that SAHA inhibits VEGF-C expression in breast cancer cellsvia transcriptional repression and this drug may exert anti-lymphangiogenic activityin cancer treatment.

oncology reports

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