EZH2-mediated concordant repression of Wnt antagonists promotes β-catenin-dependent hepatocarcinogenesis.
ABSTRACT Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the Polycomb-repressive complex 2 (PRC2) that represses gene transcription through histone H3 lysine 27 trimethylation (H3K27me3). Although EZH2 is abundantly present in various cancers, the molecular consequences leading to oncogenesis remain unclear. Here, we show that EZH2 concordantly silences the Wnt pathway antagonists operating at several subcellular compartments, which in turn activate Wnt/β-catenin signaling in hepatocellular carcinomas (HCC). Chromatin immunoprecipitation promoter array and gene expression analyses in HCCs revealed EZH2 occupancy and reduced expression of Wnt antagonists, including the growth-suppressive AXIN2, NKD1, PPP2R2B, PRICKLE1, and SFRP5. Knockdown of EZH2 reduced the promoter occupancy of PRC2, histone deacetylase 1 (HDAC1), and H3K27me3, whereas the activating histone marks were increased, leading to the transcriptional upregulation of the Wnt antagonists. Combinatorial EZH2 and HDAC inhibition dramatically reduced the levels of nuclear β-catenin, T-cell factor-dependent transcriptional activity, and downstream pro-proliferative targets CCND1 and EGFR. Functional analysis revealed that downregulation of EZH2 reduced HCC cell growth, partially through the inhibition of β-catenin signaling. Conversely, ectopic overexpression of EZH2 in immortalized hepatocytes activated Wnt/β-catenin signaling to promote cellular proliferation. In human HCCs, concomitant overexpression of EZH2 and β-catenin was observed in one-third (61/179) of cases and significantly correlated with tumor progression. Our data indicate that EZH2-mediated epigenetic silencing contributes to constitutive activation of Wnt/β-catenin signaling and consequential proliferation of HCC cells, thus representing a novel therapeutic target for this highly malignant tumor.
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ABSTRACT: Enhancer of zeste homolog 2 (EZH2) is a mammalian histone methyltransferase that contributes to the epigenetic silencing of target genes that regulate cancer cell growth and survival. It is overexpressed in hepatocellular carcinoma (HCC) with a clinical significance that remains obscure. Sorafenib, a multikinase inhibitor, has been used as a first-line therapeutic drug and shown clinical efficiency for advanced-stage HCC patients. In the present study, we found that sorafenib lowered the protein level of EZH2 through accelerating proteasome-mediated EZH2 degradation in hepatoma cells. Overexpression of EZH2 reversed sorafenib-induced cell growth arrest, cell cycle arrest, and cell apoptosis dependent on histone methyltransferase activity in hepatoma cells. More importantly, shRNA-mediated EZH2 knockdown or EZH2 inhibition with 3-deazaneplanocin A treatment promoted sorafenib-induced hepatoma cell growth arrest and apoptosis. Sorafenib altered the hepatoma epigenome by reducing EZH2 and H3K27 trimethylation. These results revealed a novel therapeutic mechanism underlying sorafenib treatment in suppressing hepatoma growth and survival by accelerating EZH2 degradation. Genetic deletion or pharmacological ablation of EZH2 made hepatoma cells more sensitive to sorafenib, which helps provide a strong framework for exploring innovative combined therapies for advanced-stage HCC patients.Cancer Science 06/2013; 104(6). · 3.48 Impact Factor
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ABSTRACT: Polycomb repressive complex 2 (PRC2) is the epigenetic regulator that induces histone H3 lysine 27 methylation (H3K27me3) and silences specific gene transcription. Enhancer of zeste homolog 2 (EZH2) is an enzymatic subunit of PRC2, and evidence shows that EZH2 plays an essential role in cancer initiation, development, progression, metastasis, and drug resistance. EZH2 expression is indeed regulated by various oncogenic transcription factors, tumor suppressor miRNAs, and cancer-associated non-coding RNA. EZH2 activity is also controlled by post-translational modifications, which are deregulated in cancer. The canonical role of EZH2 is gene silencing through H3K27me3, but accumulating evidence shows that EZH2 methlyates substrates other than histone and has methylase-independent functions. These non-canonical functions of EZH2 are shown to play a role in cancer progression. In this review, we summarize current information on the regulation and roles of EZH2 in cancer. We also discuss various therapeutic approaches to targeting EZH2.Cancer research and treatment : official journal of Korean Cancer Association. 07/2014; 46(3):209-222.
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ABSTRACT: Liver regeneration (LR) is a valuable model for studying mechanisms modulating hepatocyte proliferation. Nuclear receptors (NRs) are key players in the control of cellular functions, being ideal modulators of hepatic proliferation and carcinogenesis.PLoS ONE 01/2014; 9(8):e104449. · 3.53 Impact Factor