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: Cancer stem cells (CSCs) are rare, tumour-initiating cells that exhibit stem cell properties: capacity of self-renewal, pluripotency, highly tumorigenic potential, and resistance to therapy. Cancer stem cells have been characterised and isolated from many cancers, including breast cancer. Developmental pathways, such as the Wnt/β-catenin, Notch/γ-secretase/Jagged, Shh (sonic hedgehog), and BMP signalling pathways, which direct proliferation and differentiation of normal stem cells, have emerged as major signalling pathways that contribute to the self-renewal of stem and/or progenitor cells in a variety of organs and cancers. Deregulation of these signalling pathways is frequently linked to an epithelial-mesenchymal transition (EMT), and breast CSCs often possess properties of cells that have undergone the EMT process. Signalling networks mediated by microRNAs and EMT-inducing transcription factors tie the EMT process to regulatory networks that maintain "stemness". Recent studies have elucidated epigenetic mechanisms that control pluripotency and stemness, which allows an assessment on how embryonic and normal tissue stem cells are deregulated during cancerogenesis to give rise to CSCs. Epigenetic-based mechanisms are reversible, and the possibility of "resetting" the abnormal cancer epigenome by applying pharmacological compounds targeting epigenetic enzymes is a promising new therapeutic strategy. Chemoresistance of CSCs is frequently driven by various mechanisms, including aberrant expression/activity of ABC transporters, aldehyde dehydrogenase and anti-oncogenic proteins (i.e. BCL2, B-cell lymphoma-2), enhanced DNA damage response, activation of pro-survival signalling pathways, and epigenetic deregulations. Despite controversy surrounding the CSC hypothesis, there is substantial evidence for their role in cancer, and a number of drugs intended to specifically target CSCs have entered clinical trials.
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ABSTRACT: The β-catenin is an important effector in WNT/β-catenin signaling pathway, which exerts a crucial role in the development and progression of hepatocellular carcinoma (HCC). Some researchers have suggested that the overexpression of β-catenin in cytoplasm and/or nucleus was closely correlated to metastasis, poor differentiation and malignant phenotype of HCC while some other researchers hold opposite point. So far, no consensus was obtained on the prognostic and clinicopathological significance of cytoplasmic/nuclear β-catenin overexpression for HCCs.PLoS ONE 11/2014; 9(11):e111885. DOI:10.1371/journal.pone.0111885 · 3.53 Impact Factor
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ABSTRACT: To explore the molecular mechanism of hepatitis B virus-related and hepatitis C virus-related hepatocellular carcinoma, samples from hepatitis B virus and hepatitis C virus infected patients and the normal were compared, respectively. In both experiments, genes with high value were selected based on a genome-wide relative significance and genome-wide global significance model. Co-expression network of the selected genes was constructed, and transcription factors in the network were identified. Molecular complex detection algorithm was used to obtain sub-networks. Based on the new model, the top 300 genes were selected. Co-expression network was constructed and transcription factors were identified. We obtained two common genes FCN2 and CXCL14, and two common transcription factors RFX5 and EZH2. In hepatitis B virus experiment, cluster 1 and 3 had the higher value. In cluster 1, ten of the 17 genes and one transcription factor were all reported associated with hepatocellular carcinoma. In cluster 3, transcription factor ESR1 was reported related with hepatocellular carcinoma. In hepatitis C virus experiment, the value of cluster 3 and 4 was higher. In cluster 3, nine genes were reported to play a key role in hepatocellular carcinoma. In cluster 4, there were 5 genes in the 34 genes. To compare the relevance of a node in holding together communicating nodes, centralities based analysis was performed and we obtained some genes with high stress value. The analysis above helped us to understand the pathogenesis of hepatitis B virus and hepatitis C virus associated hepatocellular carcinoma.International Journal of Clinical and Experimental Medicine 01/2014; 7(11):4038-50. · 1.42 Impact Factor