Wnt信号通路
表观遗传学
生物
癌症干细胞
干细胞
癌症研究
细胞生物学
信号转导
遗传学
基因
作者
Tao Wang,Hong Wu,Sha Li,Zengjie Lei,Zhong-yi Qin,Liangzhi Wen,Kaijun Liu,Xingwei Wang,Yan Guo,Lei Liu,Li Lin,Constance Mao,Xiangfeng Zhu,Hualiang Xiao,Xiu‐Wu Bian,Dongfeng Chen,Chuan Xu,Bin Wang
标识
DOI:10.1016/j.canlet.2018.05.003
摘要
Tumor growth is fueled by subset of cells with stem cell properties (Cancer stem cells, CSCs). While persistent activation of Wnt/β-catenin signaling confers CSC properties, it remains unclear how epigenetic modifications regulate Wnt target genes to dictate their self-renewal. Here, we report a novel Wnt-responsive epigenetic switch for CSC maintenance through activating the stem cell transcription factor ASCL2 in gastric carcinoma (GC). We characterize ASCL2-expressing (ASCL2+) GC cells as a subset of Wnt-responsive CSCs that depend on ASCL2 for self-renewal. High-throughput RNAi screening uncovers that the histone methyltransferase SMYD3 determines H3K4me3 status at the ASCL2 locus to promote ASCL2 expression. Moreover, SMYD3 may be transcriptionally activated by the β-catenin/TCF4 complex, indicating that the SMYD3-ASCL2 axis may be an integral component of Wnt signaling. Consistently, SMYD3 maintains self-renewal and tumorigenicity of ASCL2+ CSCs largely through inducing ASCL2. Clinically, overexpression of SMYD3 and ASCL2 are associated with malignant progression and poor patient outcomes in GC. Together, these findings define a Wnt-responsive CSC pathway that could be exploited to identify essential regulators of the signaling output, and reveal SMYD3 as an epigenetic target for eliminating CSCs in human cancers.
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