Enhancer of zeste homolog 2 epigenetically silences... : Hepatology (original) (raw)
Hepatobiliary Malignancies
Enhancer of zeste homolog 2 epigenetically silences multiple tumor suppressor microRNAs to promote liver cancer metastasis
Au, Sandy Leung-Kuen1; Wong, Carmen Chak-Lui1; Lee, Joyce Man-Fong1; Fan, Dorothy Ngo-Yin1; Tsang, Felice Hoching1; Ng, Irene Oi-Lin1,*; Wong, Chun-Ming1,*
1_State Key Laboratory for Liver Research and Department of Pathology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong_
*Address reprint requests to: State Key Laboratory for Liver Research and Department of Pathology, University Pathology Building, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong
Email:[email protected]
Email:[email protected]
Received 14 September 2011; Accepted 11 February 2012
Grant sponsor: Hong Kong Research Grants Council General Research Fund; Grant Numbers: HKU 778508M HKU 782411M; Grant sponsor: Hong Kong Research Grants Council Collaborative Research Fund; Grant Numbers: HKU 1/06C HKU 7/CRG/09; Grant sponsor: Loke Yew Professor in Pathology.
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)
Copyright © 2012 American Association for the Study of Liver Diseases.