Abstract 513: Inhibition of histone deacetylase activity down-regulates urokinase plasminogen activator and matrix metalloproteinase-9 expression in gastric cancer cell lines

Abstract

Abstract Histone acetylation plays an important role in chromatin remodeling and gene expression. An imbalance of this reaction leads to aberrant behavior of cells in the cell cycle, i.e., carcinogenesis. Histone deacetylase (HDAC) inhibitors have been shown to have anti-tumor effects in clinical trials. However, the exact mechanisms by which HDAC inhibitors exert anti-tumor effects and modulate gene expression are not completely understood, and thus remain a subject of intense investigation. In the current study, we determined whether HDACs regulate urokinase plasminogen activator (uPA), matrix metalloproteinase (MMP)-9, and tumor invasion. Using cDNA microarray analysis, we showed that hepatocyte growth factor (HGF) induced HDAC-5 expression in both gastric cancer cell lines. TSA, a HDAC inhibitor, decreased HGF-induced HADC-5 expression and also repressed uPA and MMP-9 expression. We confirmed these results using HDAC-5 gene overexpressing cell lines. The number of viable cells in the cultures with or without TSA treatment was determined by the MTT assay. TSA inhibited cell proliferation in both cell lines. We characterized the effects of TSA on MMP-9-mediated proteolysis as assessed by zymography. In vitro Matrigel invasion assays showed that the HDAC inhibitor resulted in a significant decrease in cancer cell invasion. Furthermore, Gö6976, a PKC inhibitor, significantly inhibited HGF-induced HDAC-5 expression and invasion. These results demonstrated that HDACs regulate HGF-induced uPA and MMP-9 expression of gastric cancer cells, and the PKC pathway may play an important role in HGF-mediated cell invasion in gastric cancer cells, suggesting that such activities serve as anti-tumor mechanisms of the HDAC inhibitor. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 513.