EZH2 Mediates epigenetic silencing of neuroblastoma suppressor genes CASZ1, CLU, RUNX3, and NGFR.
EZH2 Mediates epigenetic silencing of neuroblastoma suppressor genes CASZ1, CLU, RUNX3, and NGFR.
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DOI：
10.1158/0008-5472.can-11-0961
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发表时间：
2012-01-01
期刊：
影响因子：
11.2
通讯作者：
Thiele CJ
中科院分区：
文献类型：
--
作者：
Wang C;Liu Z;Woo CW;Li Z;Wang L;Wei JS;Marquez VE;Bates SE;Jin Q;Khan J;Ge K;Thiele CJ
神经母细胞瘤（NB）是最常见的颅外儿童实体瘤，具有未分化状态和通常预后不良，但这些特征的基础仍然未知。在这项研究中，我们表明，上调的Polycomb复杂的组蛋白甲基转移酶EZH 2，这限制了在许多组织中的分化，是至关重要的维持未分化状态和预后不良的状态NB的表观遗传抑制多个肿瘤抑制基因。我们通过检查CASZ 1的调节来确定EZH 2的这种作用，CASZ 1是最近确定的NB肿瘤抑制基因，其异位恢复抑制NB细胞生长并诱导分化。通过RNAi介导的敲低或用3-去氮普兰诺菌素A（DZNep）的药理学抑制来降低EZH 2表达增加CASZ 1表达，抑制NB细胞生长并诱导神经突延伸。同样，EZH 2 −/−小鼠胚胎成纤维细胞（MEFs）显示CASZ 1 mRNA水平比EZH 2 +/+ MEFs高3倍。在CASZ 1表达增加的细胞中，用HDAC抑制剂处理降低了EZH 2和Polycomb复合物组分SUZ 12的表达。在稳态条件下，与CASZ 1基因结合的H3 K27 me 3和PRC 2组分富集，但在HDAC抑制剂处理后，这种富集降低。我们确定肿瘤抑制因子CLU、NGFR和RUNX 3也像NB细胞中的CASZ 1一样被EZH 2直接抑制。总之，我们的研究结果表明，NB细胞中EZH 2的异常上调沉默了几种肿瘤抑制因子，这有助于NB肿瘤未分化表型的发生和维持。
Neuroblastoma (NB) is the most common extracranial pediatric solid tumor with an undifferentiated status and generally poor prognosis, but the basis for these characteristics remains unknown. In this study, we show that upregulation of the Polycomb complex histone methytransferase EZH2, which limits differentiation in many tissues, is critical to maintain the undifferentiated state and poor prognostic status of NB by epigenetic repression of multiple tumor suppressor genes. We identified this role for EZH2 by examining the regulation of CASZ1, a recently identified NB tumor suppressor gene whose ectopic restoration inhibits NB cell growth and induces differentiation. Reducing EZH2 expression by RNAi-mediated knockdown or pharmacological inhibiton with 3-deazaneplanocin A (DZNep) increased CASZ1 expression, inhibited NB cell growth and induced neurite extension. Similarly, EZH2−/− mouse embryonic fibroblasts (MEFs) displayed 3-fold higher levels of CASZ1 mRNA compared to EZH2+/+ MEFs. In cells with increased expression of CASZ1, treatment with HDAC inhibitors decreased expression of EZH2 and the Polycomb complex component SUZ12. Under steady-state conditions H3K27me3 and PRC2 components bound to the CASZ1 gene were enriched, but this enrichment was decreased after HDAC inhibitor treatment. We determined that the tumor suppressors CLU, NGFR and RUNX3 were also directly repressed by EZH2 like CASZ1 in NB cells. Together, our findings establish that aberrant upregulation of EZH2 in NB cells silences several tumor suppressors, which contribute to the genesis and maintenance of the undifferentiated phenotype of NB tumors.