title: Inhibition of histone deacetylase activity down-regulates urokinase plasminogen activator and matrix metalloproteinase-9 expression in gastric cancer.
abstract: Histone acetylation and deacetylaion play important roles in chromatin remodeling and gene expression. An imbalance of these reactions leads to aberrant behavior of the cells in the cell cycle, which in turn contributes to 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 remain a subject of intense investigation. In the current study, we determined whether HDACs regulate urokinase plasminogen activator (uPA), matrix metalloproteinase-9 (MMP-9), and tumor invasion. Using cDNA microarray analysis, we found that hepatocyte growth factor (HGF) induced HDAC5 expression in gastric cancer cell lines, NUGC-3 and MKN-28. TSA, a HDAC inhibitor, decreased HGF-induced HADC-5 expression and also repressed uPA and MMP-9 expression. TSA inhibited cell proliferation in both cell lines. In vitro Matrigel invasion assays showed that the HDAC inhibitor decreased cancer cell invasion. Furthermore, GO6976, a PKC inhibitor, significantly inhibited not only HGF-induced HDAC5 expression but also cell invasion. These results demonstrated that HDACs regulate HGF-induced uPA and MMP-9 expression through a PKC-dependent signal pathway in gastric cancer cells. Our data probably suggest that such activities serve as anti-tumor mechanisms of the HDAC inhibitor.
authors.affiliation: Department of Hematology-Oncology, College of Medicine, Yeungnam University, Daegu, Korea. lkhee@med.yu.ac.kr
authors.forename: Kyung Hee
authors.initials: KH
authors.lastname: Lee
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Choi
authors.forename: Min Kyoung
authors.initials: MK
authors.lastname: Kim
authors.forename: Kyeong Ok
authors.initials: KO
authors.lastname: Kim
authors.forename: Byung Ik
authors.initials: BI
authors.lastname: Jang
authors.forename: Se Won
authors.initials: SW
authors.lastname: Kim
authors.forename: Sang Woon
authors.initials: SW
authors.lastname: Kim
authors.forename: Sun Kyo
authors.initials: SK
authors.lastname: Song
authors.forename: Jae-Ryong
authors.initials: JR
authors.lastname: Kim
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D018076:DNA, Complementary; D015536:Down-Regulation / Q000187:drug effects*; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000201:enzymology*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
chemical_list: D018076:DNA, Complementary; D056572:Histone Deacetylase Inhibitors; D017228:Hepatocyte Growth Factor; D014568:Urokinase-Type Plasminogen Activator; D020780:Matrix Metalloproteinase 9; C404500:HDAC5 protein, human; D006655:Histone Deacetylases