Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
Cell Rep. 2013 May 30;3(5):1567-79. doi: 10.1016/j.celrep.2013.04.021. Epub 2013 May 23.
Glioblastoma (GBM) is thought to be driven by a subpopulation of cancer stem cells (CSCs) that self-renew and recapitulate tumor heterogeneity yet remain poorly understood. Here, we present a comparative analysis of chromatin state in GBM CSCs that reveals widespread activation of genes normally held in check by Polycomb repressors. These activated targets include a large set of developmental transcription factors (TFs) whose coordinated activation is unique to the CSCs. We demonstrate that a critical factor in the set, ASCL1, activates Wnt signaling by repressing the negative regulator DKK1. We show that ASCL1 is essential for the maintenance and in vivo tumorigenicity of GBM CSCs. Genome-wide binding profiles for ASCL1 and the Wnt effector LEF-1 provide mechanistic insight and suggest widespread interactions between the TF module and the signaling pathway. Our findings demonstrate regulatory connections among ASCL1, Wnt signaling, and collaborating TFs that are essential for the maintenance and tumorigenicity of GBM CSCs.
胶质母细胞瘤（GBM）被认为是由癌症干细胞（CSC）亚群驱动的，这些干细胞自我更新并再现肿瘤异质性，但仍知之甚少。在这里，我们对 GBM CSC 中的染色质状态进行了比较分析，揭示了广泛激活通常被 Polycomb 抑制物抑制的基因。这些激活的靶标包括一大组发育转录因子（TFs），它们的协调激活是 CSC 所特有的。我们证明，该集合中的关键因素 ASCL1 通过抑制负调节剂 DKK1 来激活 Wnt 信号。我们表明，ASCL1 对于 GBM CSC 的维持和体内致瘤性是必不可少的。ASCL1 和 Wnt 效应因子 LEF-1 的全基因组结合图谱提供了机制上的见解，并表明 TF 模块和信号通路之间存在广泛的相互作用。我们的研究结果表明，ASCL1、Wnt 信号和协作 TF 之间的调控联系对于 GBM CSC 的维持和致瘤性是必不可少的。
