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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >EZH2 is a mediator of EWS/FLI1 driven tumor growth and metastasis blocking endothelial and neuro-ectodermal differentiation
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EZH2 is a mediator of EWS/FLI1 driven tumor growth and metastasis blocking endothelial and neuro-ectodermal differentiation

机译：EZH2是EWS / FLI1驱动的肿瘤生长和转移的介体，阻断内皮和神经-外胚层分化

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摘要

Ewing tumors (ET) are highly malignant, localized in bone or soft tissue, and are molecularly defined by ews/ets translocations. DNA microarray analysis revealed a relationship of ET to both endothe-lium and fetal neural crest. We identified expression of histone methyltransferase enhancer of Zeste, Drosophila, Homolog 2 (EZH2) to be increased in ET. Suppressive activity of EZH2 maintains sternness in normal and malignant cells. Here, we found EWS/FLI1 bound to the EZH2 promoter in vivo, and induced EZH2 expression in ET and mesenchymal stem cells. Down-regulation of EZH2 by RNA interference in ET suppressed oncogenic transformation by inhibiting clonogenicity in vitro. Similarly, tumor development and metastasis was suppressed in immunodeficient Rag2~(-/-)γ_c~(-/-) mice. EZH2-mediated gene silencing was shown to be dependent on histone deacetylase (HDAC) activity. Subsequent microarray analysis of EZH2 knock down, HDAC-inhibitor treatment and confirmation in independent assays revealed an undifferentiated phenotype maintained by EZH2 in ET. EZH2 regulated sternness genes such as nerve growth factor receptor (NGFR), as well as genes involved in neuroectodermal and endothelial differentiation (EMP1, EPHB2, GFAP, and GAP43). These data suggest that EZH2 might have a central role in ET pathology by shaping the oncoge-nicity and stem cell phenotype of this tumor.
机译：尤因肿瘤（ET）是高度恶性的，定位于骨骼或软组织中，并在分子/母体易位中被分子定义。 DNA微阵列分析显示ET与内皮和胎儿神经c都有关系。我们鉴定到在ET中，Zeste，果蝇，同源2（EZH2）的组蛋白甲基转移酶增强子的表达增加。在正常和恶性细胞中，EZH2的抑制活性维持了严峻性。在这里，我们发现EWS / FLI1在体内与EZH2启动子结合，并诱导ET和间充质干细胞中EZH2的表达。 RNA干扰在ET中对EZH2的下调通过在体外抑制克隆形成性来抑制致癌转化。同样，在免疫缺陷的Rag2〜（-/-）γ_c〜（-/-）小鼠中，肿瘤的发展和转移受到抑制。 EZH2介导的基因沉默显示依赖于组蛋白脱乙酰基酶（HDAC）活性。随后的EZH2基因敲除，HDAC抑制剂治疗和独立测定中的确证的微阵列分析揭示了EZH2在ET中维持的未分化表型。 EZH2调节严厉性基因，例如神经生长因子受体（NGFR），以及涉及神经外胚层和内皮分化的基因（EMP1，EPHB2，GFAP和GAP43）。这些数据表明，EZH2可能通过塑造该肿瘤的癌性和干细胞表型而在ET病理学中发挥重要作用。

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    Guenther H. S. Richter; Stephanie Plehm; Annette Fasan; Sabine Roessler; Rebekka Unland; Idriss M. Bennani-Baiti; Marc Hotfilder; Diana Loewel; Irene von Luettichau; Ilona Mossbrugger; Leticia Quintanilla-Martinez; Heinrich Kovar; Martin S. Staege; Carsten Mueller-Tidow; Stefan Burdach;

  • 作者单位

    Laboratory for Functional Genomics and Transplantation Biology, Department of Pediatrics, Technische Universitaet Munchen and Pediatric Oncology Center, 81664 Munich, Germany;

    Laboratory for Functional Genomics and Transplantation Biology, Department of Pediatrics, Technische Universitaet Munchen and Pediatric Oncology Center, 81664 Munich, Germany;

    Laboratory for Functional Genomics and Transplantation Biology, Department of Pediatrics, Technische Universitaet Munchen and Pediatric Oncology Center, 81664 Munich, Germany;

    Laboratory for Functional Genomics and Transplantation Biology, Department of Pediatrics, Technische Universitaet Munchen and Pediatric Oncology Center, 81664 Munich, Germany;

    Department of Medicine, Hematology, and Oncology, and Interdisciplinary Center for Clinical Research (IZKF), University of Muenster, 48149 Muenster, Gemany Department of Pediatric Hematology and Oncology, University Children's Hospital, University of Muenster, 48149 Muenster, Gemany;

    Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, 1090 Vienna, Austria;

    Department of Pediatric Hematology and Oncology, University Children's Hospital, University of Muenster, 48149 Muenster, Gemany;

    Laboratory for Functional Genomics and Transplantation Biology, Department of Pediatrics, Technische Universitaet Munchen and Pediatric Oncology Center, 81664 Munich, Germany;

    Laboratory for Functional Genomics and Transplantation Biology, Department of Pediatrics, Technische Universitaet Munchen and Pediatric Oncology Center, 81664 Munich, Germany;

    Institute of Pathology, Helmholtz Center Munich, German Research Center for Environmental Health, D-85764 Neuherberg, Germany;

    Institute of Pathology, Helmholtz Center Munich, German Research Center for Environmental Health, D-85764 Neuherberg, Germany;

    Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, 1090 Vienna, Austria;

    Department of Pediatrics, Martin-Luther-University Halle-Wittenberg, 06097 Halle, Germany;

    Department of Medicine, Hematology, and Oncology, and Interdisciplinary Center for Clinical Research (IZKF), University of Muenster, 48149 Muenster, Gemany;

    Laboratory for Functional Genomics and Transplantation Biology, Department of Pediatrics, Technische Universitaet Munchen and Pediatric Oncology Center, 81664 Munich, Germany;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    epigenetic regulation; ewing tumor; sternness;

    机译：表观遗传调控尤因肿瘤严厉;

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