Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells
Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells
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DOI：
10.1016/j.ccr.2007.12.005
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发表时间：
2008-01-01
期刊：
影响因子：
50.3
通讯作者：
Fine, Howard A.
中科院分区：
文献类型：
--
作者：
Lee, Jeongwu;Son, Myung Jin;Fine, Howard A.
尽管具有干细胞样特性的肿瘤起始细胞(TIC)与正常神经干细胞相似，但我们假设它们的分化潜能可能存在差异。我们现在证明，骨形态发生蛋白(BMP)和睫状神经营养因子(CNTF)介导的JAK/STAT依赖的星形胶质细胞分化都受到损害，这是由于EZH2依赖的BMP受体1B(BMPR1B)在一组胶质母细胞瘤患者中的表观遗传沉默。通过转基因表达或启动子去甲基化强制表达BMPR1B可恢复其分化能力，并导致其致瘤性丧失。我们认为，在胶质母细胞瘤的一个亚组中，BMP发育途径的解除调节有助于它们的致瘤性，既通过使TIC对正常分化信号脱敏，也通过将其他细胞抑制信号转换为促增殖信号。
Despite similarities between tumor-initiating cells with stem-like properties (TICs) and normal neural stem cells, we hypothesized that there may be differences in their differentiation potentials. We now demonstrate that both bone morphogenetic protein (BMP)-mediated and ciliary neurotrophic factor (CNTF)-mediated Jak/STAT-dependent astroglial differentiation is impaired due to EZH2-dependent epigenetic silencing of BMP receptor 1B (BMPR1B) in a subset of glioblastoma TICs. Forced expression of BMPR1B either by transgene expression or demethylation of the promoter restores their differentiation capabilities and induces loss of their tumorigenicity. We propose that deregulation of the BMP developmental pathway in a subset of glioblastoma TICs contributes to their tumorigenicity both by desensitizing TICs to normal differentiation cues and by converting otherwise cytostatic signals to proproliferative signals.