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Inhibition of histone deacetylase activity down-regulates urokinase plasminogen activator and matrix metalloproteinase-9 expression in gastric cancer

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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.

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Abbreviations

HGF:

Hepatocyte growth factor

uPA:

Urokinase plasminogen activator

HDAC:

Histone deacetylase

MMP:

Matrix metalloproteinase

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Acknowledgments

This study was supported by the Korea Science and Engineering Foundation (KOSEF) NCRC grant funded by the Korea government (MEST; No. R15-2004-033-05001-0).

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Authors and Affiliations

  1. Department of Hematology-Oncology, College of Medicine, Yeungnam University, Daegu, Korea

    Kyung Hee Lee, Eun Young Choi & Min Kyoung Kim

  2. Department of Gastro-Enterology, College of Medicine, Yeungnam University, Daegu, Korea

    Kyeong Ok Kim & Byung Ik Jang

  3. Department of Surgery, College of Medicine, Yeungnam University, Daegu, Korea

    Se Won Kim, Sang Woon Kim & Sun Kyo Song

  4. Department of Biochemistry and Molecular Biology, College of Medicine, Yeungnam University, 317-1 Daemyung-Dong, Daegu, 705-717, Republic of Korea

    Jae-Ryong Kim

  5. Aging-associated Vascular Disease Research Center, College of Medicine, Yeungnam University, Daegu, Korea

    Jae-Ryong Kim

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  1. Kyung Hee Lee
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Correspondence to Jae-Ryong Kim.

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Lee, K.H., Choi, E.Y., Kim, M.K. et al. Inhibition of histone deacetylase activity down-regulates urokinase plasminogen activator and matrix metalloproteinase-9 expression in gastric cancer. Mol Cell Biochem 343, 163–171 (2010). https://doi.org/10.1007/s11010-010-0510-x

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  • DOI: https://doi.org/10.1007/s11010-010-0510-x

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