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A histone deacetylase inhibitor, largazole, decreases liver fibrosis and angiogenesis by inhibiting transforming growth factor-β and vascular endothelial growth factor signalling

Authors

  • Yuqing Liu,

    1. Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hong Kong SAR, China
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    • Joint first author.
  • Zhuo Wang,

    1. Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hong Kong SAR, China
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    • Joint first author.
  • Jianing Wang,

    1. Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hong Kong SAR, China
    2. Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
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  • Wingchi Lam,

    1. Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hong Kong SAR, China
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  • Shuqin Kwong,

    1. Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hong Kong SAR, China
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  • Furong Li,

    1. Clinical Medicinal Research Center, The Second Clinic Medicine College, Shenzhen People's Hospital, Jinan University, Shenzhen, China
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  • Scott L. Friedman,

    1. Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY, USA
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  • Shuyan Zhou,

    1. Clinical Medicinal Research Center, The Second Clinic Medicine College, Shenzhen People's Hospital, Jinan University, Shenzhen, China
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  • Qi Ren,

    1. Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
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  • Zhengshuang Xu,

    1. Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
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  • XinGen Wang,

    1. Clinical Medicinal Research Center, The Second Clinic Medicine College, Shenzhen People's Hospital, Jinan University, Shenzhen, China
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  • Ling Ji,

    1. Clinical Medicinal Research Center, The Second Clinic Medicine College, Shenzhen People's Hospital, Jinan University, Shenzhen, China
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  • Shoubin Tang,

    1. Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
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  • Hui Zhang,

    1. Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
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  • Eric L. Lui,

    1. Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hong Kong SAR, China
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  • Tao Ye

    Corresponding author
    1. Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
    • Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hong Kong SAR, China
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  • Xiaojuan Sun and Zhiming Cai also contributed to this paper by performing work in the treatment of experimental liver fibrosis by largazole and by measuring the serum marker.

Correspondence

Tao Ye, Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hong Kong SAR, China

Tel: +852 34008722

Fax: +852 23649932

e-mails: bctaoye@inet.polyu.edu.hk

Abstract

Background & Aims

Largazole is a novel histone deacetylase (HDAC) inhibitor. This study investigated the effects of largazole against liver fibrosis.

Methods

The in vitro effects of largazole were examined using hepatic stellate cells (HSCs). In vivo effects of largazole were studied using a mouse liver fibrotic model induced by CCl4.

Results

Largazole augmented acetylation of histone H3 (H3) and histone H4 (H4) in HSCs. It directly inhibited the activation of HSCs owing to HDAC inhibitory activity as the antifibrotic effect of largazole was significantly decreased in cells with HDAC1, HDAC2 and HDAC3 knockdown. Largazole also induced apoptosis of HSCs. Largazole not only inhibited the expression of TGFβR2, but also reduced phosphorylation of Smad2 and Akt induced by TGF-β1. Largazole also inhibited the expression of vascular endothelial growth factor (VEGF) and its receptor. VEGF-induced proliferation of HSCs and activation of Akt and p38MAPK were also suppressed by largazole. In vivo, largazole reduced the expression of collagen I, α-smooth muscle actin and tissue inhibitor of metalloproteinase-1 in CCl4–induced fibrosis, and these antifibrotic effects were associated with increased acetylation of H3 and H4. Largazole also induced HSCs to undergo apoptosis in vivo, which was correlated with downregulation of bcl-2 and bcl-xL. Furthermore, largazole inhibited angiogenesis in vivo as evidenced by reduced expression of CD34, VEGF and VEGFR. In addition to its antifibrotic activity, the drug reduced inflammatory activity in CCl4-induced liver fibrosis.

Conclusions

Our findings revealed a novel role of largazole in the treatment of liver fibrosis. Through multiple mechanisms, largazole could be a potentially effective antifibrotic agent.

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