The lncRNA H19 positively affects the tumorigenic properties of glioblastoma cells and contributes to NKD1 repression through the recruitment of EZH2 on its promoter.
The lncRNA H19 positively affects the tumorigenic properties of glioblastoma cells and contributes to NKD1 repression through the recruitment of EZH2 on its promoter.
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DOI：
10.18632/oncotarget.24496
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发表时间：
2018-03-20
期刊：
影响因子：
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通讯作者：
Ciafrè SA
中科院分区：
文献类型：
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作者：
Fazi B;Garbo S;Toschi N;Mangiola A;Lombari M;Sicari D;Battistelli C;Galardi S;Michienzi A;Trevisi G;Harari-Steinfeld R;Cicchini C;Ciafrè SA
胶质母细胞瘤是一种原发性脑肿瘤，其特点是预后不可避免地令人沮丧，但在很大程度上仍不清楚的分子事件促使人们进行研究。长链非编码 RNA 作为基因表达调节因子的重要性最近变得显而易见。其中，H19 在多种类型的人类肿瘤中具有公认的致癌作用，并被证明与胶质母细胞瘤细胞的某些致癌方面相关。在这里，我们假设在胶质母细胞瘤中 H19 通过与 PRC2 复合物的催化亚基 EZH2 相互作用来发挥其功能。通过对 12 个胶质母细胞瘤样本的 SAGE 数据集进行因子分析，我们发现胶质母细胞瘤组织中的 H19 表达与参与胶质母细胞瘤生长和进展的几个基因的表达相关。 H19 敲低降低了两种不同的人胶质母细胞瘤细胞系的活力、迁移和侵袭性。最重要的是，我们通过证明 H19 的表达与 Wnt 通路负调节因子 NKD1 的表达呈负相关，提供了关于 H19 在胶质母细胞瘤细胞中的作用的机制观点，表明 H19 可能通过 EZH2 诱导的启动子 H3K27 三甲基化来调节 NKD1 转录。事实上，我们发现 H19 在胶质母细胞瘤细胞中结合 EZH2，并且 H19 沉默会损害 EZH2 与 NKD1 和其他启动子的结合。在这项工作中，我们将 H19 描述为 EZH2 执行的表观遗传调节程序的一部分，该程序导致 Nkd1 的抑制。我们相信，我们的结果可以为胶质母细胞瘤中 H19 功能的复杂难题提供新的线索。
The still largely obscure molecular events in the glioblastoma oncogenesis, a primary brain tumor characterized by an inevitably dismal prognosis, impel for investigation. The importance of Long noncoding RNAs as regulators of gene expression has recently become evident. Among them, H19 has a recognized oncogenic role in several types of human tumors and was shown to correlate to some oncogenic aspects of glioblastoma cells. Here we, hypothesyze that in glioblastoma H19 exerts its function through the interaction with the catalytic subunit of the PRC2 complex, EZH2. By employing a factor analysis on a SAGE dataset of 12 glioblastoma samples, we show that H19 expression in glioblastoma tissues correlates with that of several genes involved in glioblastoma growth and progression. H19 knock-down reduces viability, migration and invasiveness of two distinct human glioblastoma cell lines. Most importantly, we provide a mechanistic perspective about the role of H19 in glioblastoma cells, by showing that its expression is inversely linked to that of NKD1, a negative regulator of Wnt pathway, suggesting that H19 might regulate NKD1 transcription via EZH2-induced H3K27 trimethylation of its promoter. Indeed, we showed that H19 binds EZH2 in glioblastoma cells, and that EZH2 binding to NKD1 and other promoters is impaired by H19 silencing. In this work we describe H19 as part of an epigenetic modulation program executed by EZH2, that results in the repression of Nkd1. We believe that our results can provide a new piece to the complex puzzle of H19 function in glioblastoma.