The Gene for Polycomb Group Protein Enhancer of Zeste Homolog 2 (EZH2) is Amplified in Late-Stage Prostate Cancer

Cancer Genetics, Institute of Medical Technology, University of Tampere and Tampere University Hospital, Tampere, Finland.
Genes Chromosomes and Cancer (Impact Factor: 4.04). 07/2006; 45(7):639-45. DOI: 10.1002/gcc.20327
Source: PubMed


Overexpression of the polycomb group protein enhancer of zeste homologue 2 (EZH2) has been found in several malignancies, including prostate cancer, with an aggressive phenotype. Amplification of the gene has previously been demonstrated in several malignancies, but not in prostate cancer. Our goal was to evaluate the gene copy number and expression alterations of EZH2 in prostate cancer. The copy number of EZH2 in cell lines (LNCaP, DU145, PC-3, 22Rv1), xenografts (n = 10), and clinical tumors (n = 191) was studied with fluorescence in situ hybridization. All cell lines had a gain of EZH2. Eight of the ten xenografts showed an increased copy number of the gene, including one case of high-level amplification (>or=5 copies of the gene and EZH2/centromere ratio >or=2). 34/125 (27%) of untreated prostate carcinomas showed increased copy number, but only one case of low-level amplification (>or=5 copies of the gene and EZH2/centromere ratio <2), whereas half (25/46) of the hormone-refractory carcinomas showed increased copy number, including seven cases of low-level amplification and three cases of high-level amplification (P < 0.0001). Expression of EZH2 was significantly (P = 0.0009) higher in hormone-refractory prostate cancer compared with that in benign prostatic hyperplasia or untreated cancer, according to quantitative real-time RT-PCR assay. Also, the expression of EZH2 protein was found to be higher in hormone-refractory tumors than in hormone-naïve tumors by immunohistochemistry. The EZH2 gene amplification was significantly (P < 0.05) associated with increased EZH2 protein expression. The data show that amplification of the EZH2 gene is rare in early prostate cancer, whereas a fraction of late-stage tumors contains the gene amplification leading to the overexpression of the gene, thus indicating the importance of EZH2 in the progression of prostate cancer.

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Available from: Outi R Saramäki, Jan 19, 2015
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    • "Microarray studies have linked overexpression of EZH2 to PCa (Varambally et al., 2002). More than half of the hormone-refractory PCa possess increased copies of EZH2 gene, which correlates with high expression levels of EZH2 protein, whereas its amplification and overexpression is rare in early stage PCa, highlighting its potential function in PCa progression (Saramäki et al., 2006). "
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    ABSTRACT: The histone methyltransferase EZH2 (enhancer of zeste homolog 2) plays critical roles in prostate cancer (PCa) development and is a potential target for PCa treatment. Triptolide possesses anti-tumor activity, but it is unknown whether its therapeutic effect relates with EZH2 in PCa. Here we described EZH2 as a target for Triptolide in PCa cells. Our data showed that Triptolide suppressed PCa cell growth and reduced the expression of EZH2. Overexpression of EZH2 attenuated the Triptolide induced cell growth inhibition. Moreover, Triptolide treatment of PC-3 cells resulted in elevated mRNA levels of target genes (ADRB2, CDH1, CDKN2A and DAB2IP) negatively regulated by EZH2 as well as reduced mRNA levelsan of EZH2 positively regulated gene (cyclin D1). Our findings suggest the PCa cell growth inhibition mediated by Triptolide might be associated with downregulation of EZH2 expression and the subsequent modulation of target genes.
    Asian Pacific journal of cancer prevention: APJCP 10/2013; 14(10):5663-9. DOI:10.7314/APJCP.2013.14.10.5663 · 2.51 Impact Factor
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    • "The enhancer of zeste homolog 2 (EZH2, also called histone lysine methyltransferase) is located at chromosome 7q35 and encodes a member of the Polycomb group proteins [7], which regulate gene expression via epigenetic modification of chromatin structure including inducing histone acetylation and methylation [7,8]. Previous studies showed that EZH2 is overexpressed in a broad range of tumors [9,10]. "
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    ABSTRACT: Background The enhancer of zeste homolog 2 (EZH2) was found to be overexpressed and associated with tumor metastasis in esophageal squamous cell carcinoma (ESCC). On the other hand, it was reported that miR-26a, miR-98, miR-101, miR-124, miR-138 and miR-214 could inhibit the expression of EZH2 in some tumors. However, the role of miRNAs in the regulation of EZH2 expression in human ESCC has not been documented. The aim of this study was to determine the role of these miRNAs in the regulation of tumor metastasis via EZH2 overexpression in human ESCC. Methods and results The expression of these miRNAs and EZH2 mRNA were examined by qPCR and the expression of EZH2 protein was detected by western blot. The role of these miRNAs in migration and invasion was studied in ESCC cell line (Eca109) transfected with miRNA mimics or cotransfected with miRNA mimics and pcDNA-EZH2 plasmid (without the 3’-UTR of EZH2). Through clinical investigation, we found that miR-98 and miR-214 expression was significantly lower in ESCC tissues than in matched normal tissues, and the expression level of miR-98 and miR-214 was inversely correlated to EZH2 protein expression and the clinical features such as pathological grade, tumor stage and lymph node metastasis in ESCC. In Eca109 cells, overexpression of miR-98 and miR-214 significantly inhibited the migration and invasion of ESCC cells, which was reversed by transfection of EZH2. Conclusions These findings suggest that decreased expression of miR-98 and miR-214 might promote metastasis of human ESCC by inducing accumulation of EZH2 protein.
    Molecular Cancer 08/2012; 11(1):51. DOI:10.1186/1476-4598-11-51 · 4.26 Impact Factor
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    • "Additional studies show increased Ezh2, Suz12 level, and H3K27me3 formation in immortalized/transformed skin cancer cell lines including A431, SCC-13, and HaCaT cells (Balasubramanian et al., 2010), and that Ezh2 knockdown reduces H3K27me3 formation and this is associated with reduced SCC-13 cell proliferation and survival. Ezh2 is an example of a PRC2 protein that is overexpressed in tumors (Varambally et al., 2002; Raaphorst et al., 2003; Raman et al., 2005; Sudo et al., 2005; Saramaki et al., 2006). "
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    ABSTRACT: The Polycomb group (PcG) proteins are epigenetic suppressors of gene expression that function through modification of histones to change chromatin structure and modulate gene expression and cell behavior. Recent studies show that PcG proteins are expressed in epidermis, that their levels change during differentiation and in disease states, and that PcG expression is regulated by agents that influence cell proliferation and survival. The results indicate that PcG proteins regulate keratinocyte cell-cycle progression, apoptosis, senescence, and differentiation. These proteins are expressed in progenitor cells, in the basal layer, and in suprabasal keratinocytes, and the level, timing, and distribution of expression suggest that the PcG proteins have a central role in maintaining the balance between cell survival and death in multiple epidermal compartments. Additional studies indicate an important role in skin cancer progression.
    Journal of Investigative Dermatology 11/2010; 131(2):295-301. DOI:10.1038/jid.2010.318 · 7.22 Impact Factor
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