Inhibition of EZH2 suppresses self-renewal and induces radiation sensitivity in atypical rhabdoid teratoid tumor cells
Inhibition of EZH2 suppresses self-renewal and induces radiation sensitivity in atypical rhabdoid teratoid tumor cells
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DOI：
10.1093/neuonc/nos285
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发表时间：
2013-02-01
期刊：
影响因子：
15.9
通讯作者：
Vibhakar, Rajeev
中科院分区：
文献类型：
--
作者：
Alimova, Irina;Birks, Diane K.;Vibhakar, Rajeev
介绍。 Polycomb 抑制复合物 2 (PRC2) 亚基 Zeste 2 增强子 (EZH2) 的过度表达发生在多种恶性肿瘤中，包括前列腺癌、乳腺癌、髓母细胞瘤和多形性胶质母细胞瘤。最近的证据表明 EZH2 也可能在横纹肌样瘤中发挥作用。非典型畸胎瘤/横纹肌样瘤 (ATRT) 是一种罕见的高级胚胎性脑肿瘤，最常见于幼儿，预后非常差。 ATRT 的特点是缺乏染色质重塑蛋白 SMARCB1。鉴于 EZH2 在调节表观遗传变化中的作用，我们研究了 EZH2 在 ATRT 中的作用。方法。使用微阵列分析评估 ATRT 肿瘤样本中 EZH2 的表达。我们使用 shRNA 和 EZH2 的化学抑制剂来检查 EZH2 抑制对细胞生长、增殖和肿瘤细胞自我更新的影响。结果。在这里，我们发现通过 RNAi 或药物抑制来靶向破坏 EZH2 会强烈损害 ATRT 细胞的生长，抑制肿瘤细胞的自我更新，诱导细胞凋亡，并有效地使这些细胞对辐射敏感。通过转录因子活性的功能分析，我们发现 ATRT 细胞中 EZH2 缺失后细胞周期蛋白 D1-E2F 轴受到抑制。结论。我们的观察结果证明，EZH2 破坏会改变细胞周期进程，并且可能是 ATRT 中重要的新治疗靶点，特别是与放射治疗相结合。
Introduction. Overexpression of the Polycomb repressive complex 2 (PRC2) subunit Enhancer of Zeste 2 (EZH2) occurs in several malignancies, including prostate cancer, breast cancer, medulloblastoma, and glioblastoma multiforme. Recent evidence suggests that EZH2 may also have a role in rhabdoid tumors. Atypical teratoid/rhabdoid tumor (ATRT) is a rare, high-grade embryonal brain tumor that occurs most commonly in young children and carries a very poor prognosis. ATRTs are characterized by absence of the chromatin remodeling protein SMARCB1. Given the role of EZH2 in regulating epigenetic changes, we investigated the role of EZH2 in ATRT.Methods. Microarray analysis was used to evaluate expression of EZH2 in ATRT tumor samples. We used shRNA and a chemical inhibitor of EZH2 to examine the impact of EZH2 inhibition on cell growth, proliferation, and tumor cell self-renewal.Results. Here, we show that targeted disruption of EZH2 by RNAi or pharmacologic inhibition strongly impairs ATRT cell growth, suppresses tumor cell self-renewal, induces apoptosis, and potently sensitizes these cells to radiation. Using functional analysis of transcription factor activity, we found the cyclin D1-E2F axis to be repressed after EZH2 depletion in ATRT cells.Conclusions. Our observations provide evidence that EZH2 disruption alters cell cycle progression and may be an important new therapeutic target, particularly in combination with radiation, in ATRT.