Inhibition of histone deacetylase activity down-regulates urokinase plasminogen activator and matrix metalloproteinase-9 expression in gastric cancer.
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.
Lee
Kyung Hee
KH
Department of Hematology-Oncology, College of Medicine, Yeungnam University, Daegu, Korea. lkhee@med.yu.ac.kr
Choi
Eun Young
EY
Kim
Min Kyoung
MK
Kim
Kyeong Ok
KO
Jang
Byung Ik
BI
Kim
Se Won
SW
Kim
Sang Woon
SW
Song
Sun Kyo
SK
Kim
Jae-Ryong
JR
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*
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