Curcumin up-regulates phosphatase and tensin homologue deleted on chromosome 10 through microRNA-mediated control of DNA methylation – a novel mechanism suppressing liver fibrosis

Authors

  • Jianjian Zheng,

    1. Wenzhou Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, China
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  • Cunzao Wu,

    1. Institute of Organ Transplantation, The First Affiliated Hospital of Wenzhou Medical University, China
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  • Zhuo Lin,

    1. Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, China
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  • Yong Guo,

    1. Institute of Organ Transplantation, The First Affiliated Hospital of Wenzhou Medical University, China
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  • Liang Shi,

    1. Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, China
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  • Peihong Dong,

    1. Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, China
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  • Zhongqiu Lu,

    1. Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, China
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  • Shenmeng Gao,

    1. Laboratory of Internal Medicine, The First Affiliated Hospital of Wenzhou Medical University, China
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  • Yi Liao,

    1. Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, China
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  • Bicheng Chen,

    Corresponding author
    1. Wenzhou Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, China
    • Correspondence

      F. Yu and B. Chen, Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, No. 2 Fuxue Lane, Wenzhou, Zhejiang, China; Wenzhou Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, No. 2 Fuxu  Lane, Wenzhou, Zhejiang, China

      Fax: +86 577 88078262

      Tel: +86 577 88078232

      E-mail: tjyufujun@163.com; fire717@163.com

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    • These authors contributed equally to this work.
  • Fujun Yu

    Corresponding author
    1. Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, China
    • Correspondence

      F. Yu and B. Chen, Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, No. 2 Fuxue Lane, Wenzhou, Zhejiang, China; Wenzhou Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, No. 2 Fuxu  Lane, Wenzhou, Zhejiang, China

      Fax: +86 577 88078262

      Tel: +86 577 88078232

      E-mail: tjyufujun@163.com; fire717@163.com

    Search for more papers by this author
    • These authors contributed equally to this work.

Abstract

Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) has been reported to play a role in the suppression of activated hepatic stellate cells (HSCs). Moreover, it has been demonstrated that hypermethylation of the PTEN promoter is responsible for the loss of PTEN expression during HSC activation. Methylation is now established as a fundamental regulator of gene transcription. MicroRNAs (miRNAs), which can control gene expression by binding to their target genes for degradation and/or translational repression, were found to be involved in liver fibrosis. However, the mechanism responsible for miRNA-mediated epigenetic regulation in liver fibrosis still remained unclear. In the present study, curcumin treatment significantly resulted in the inhibition of cell proliferation and an increase in the apoptosis rate through the up-regulation of PTEN associated with a decreased DNA methylation level. Only DNA methyltransferase 3b (DNMT3b) was reduced in vivo and in vitro after curcumin treatment. Further studies were performed aiming to confirm that the knockdown of DNMT3b enhanced the loss of PTEN methylation by curcumin. In addition, miR-29b was involved in the hypomethylation of PTEN by curcumin. MiR-29b not only was increased by curcumin in activated HSCs, but also was confirmed to target DNMT3b by luciferase activity assays. Curcumin-mediated PTEN up-regulation, DNMT3b down-regulation and PTEN hypomethylation were all attenuated by miR-29b inhibitor. Collectively, it is demonstrated that curcumin can up-regulate miR-29b expression, resulting in DNMT3b down-regulation in HSCs and epigenetically-regulated PTEN involved in the suppression of activated HSCs. These results indicate that miRNA-mediated epigenetic regulation may be a novel mechanism suppressing liver fibrosis.

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