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Enhancer of zeste homolog 2 epigenetically silences multiple tumor suppressor microRNAs to promote liver cancer metastasis

Authors

  • Sandy Leung-Kuen Au,

    1. State Key Laboratory for Liver Research and Department of Pathology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
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  • Carmen Chak-Lui Wong,

    1. State Key Laboratory for Liver Research and Department of Pathology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
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  • Joyce Man-Fong Lee,

    1. State Key Laboratory for Liver Research and Department of Pathology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
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  • Dorothy Ngo-Yin Fan,

    1. State Key Laboratory for Liver Research and Department of Pathology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
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  • Felice Hoching Tsang,

    1. State Key Laboratory for Liver Research and Department of Pathology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
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  • Irene Oi-Lin Ng,

    Corresponding author
    1. State Key Laboratory for Liver Research and Department of Pathology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
    • State Key Laboratory for Liver Research and Department of Pathology, University Pathology Building, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
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  • Chun-Ming Wong

    Corresponding author
    1. State Key Laboratory for Liver Research and Department of Pathology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
    • State Key Laboratory for Liver Research and Department of Pathology, University Pathology Building, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
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  • Potential conflict of interest: Nothing to report.

Abstract

Epigenetic alterations and microRNA (miRNA) deregulation are common in hepatocellular carcinoma (HCC). The histone H3 lysine 27 (H3K27) tri-methylating enzyme, enhancer of zeste homolog 2 (EZH2) mediates epigenetic silencing of gene expression and is frequently up-regulated in human cancers. In this study we aimed to delineate the implications of EZH2 up-regulation in miRNA deregulation and HCC metastasis. Expressions of a total of 90 epigenetic regulators were first determined in 38 pairs of primary HCCs and their corresponding nontumorous livers. We identified EZH2 and its associated polycomb repressive complex 2 (PRC2) as one of the most significantly deregulated epigenetic regulators in primary HCC samples. Up-regulation of EZH2 was next confirmed in 69.5% (41/59) of primary HCCs. Clinicopathologically, EZH2 up-regulation was associated with HCC progression and multiple HCC metastatic features, including venous invasion (P = 0.043), direct liver invasion (P = 0.014), and absence of tumor encapsulation (P = 0.043). We further demonstrated that knockdown of EZH2 in HCC cell lines reduced the global levels of tri-methylated H3K27, and suppressed HCC motility in vitro and pulmonary metastasis in a nude mouse model. By interrogating the miRNA expression profile in EZH2-knockdown cell lines and primary HCC samples, we identified a subset of miRNA that was epigenetically suppressed by EZH2 in human HCC. These included well-characterized tumor-suppressor miRNAs, such as miR-139-5p, miR-125b, miR-101, let-7c, and miR-200b. Pathway enrichment analysis revealed a common regulatory role of these EZH2-silenced miRNAs in modulating cell motility and metastasis-related pathways. Our findings suggest that EZH2 exerts its prometastatic function by way of epigenetic silencing of multiple tumor suppressor miRNAs. Conclusion: Our study demonstrated that EZH2 epigenetically silenced multiple miRNAs that negatively regulate HCC metastasis. (HEPATOLOGY 2012)

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