SMYD3 controls a Wnt-responsive epigenetic switch for ASCL2 activation and cancer stem cell maintenance
SMYD3 controls a Wnt-responsive epigenetic switch for ASCL2 activation and cancer stem cell maintenance
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SMYD3 控制 Wnt 响应表观遗传开关，用于 ASCL2 激活和癌症干细胞维持
DOI：
10.1016/j.canlet.2018.05.003
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发表时间：
2018-01-01
期刊：
影响因子：
9.7
通讯作者：
Wang, Bin
中科院分区：
文献类型：
--
作者：
Wang, Tao;Wu, Hong;Wang, Bin
肿瘤生长由具有干细胞特性的细胞亚群（癌症干细胞，CSC）推动。虽然Wnt/β-连环蛋白信号传导的持续激活赋予CSC特性，但仍不清楚表观遗传修饰如何调节Wnt靶基因以决定其自我更新。在这里，我们报告了一种新的Wnt反应性表观遗传开关，通过激活胃癌（GC）中的干细胞转录因子ASCL 2来维持CSC。我们将表达ASCL 2（ASCL 2（+））的GC细胞表征为依赖于ASCL 2进行自我更新的Wnt响应性CSC的子集。高通量RNAi筛选揭示了组蛋白甲基转移酶SMYD 3决定了ASCL 2位点的H3 K4 me 3状态以促进ASCL 2表达。此外，SMYD 3可能被β-连环蛋白/TCF 4复合物转录激活，表明SMYD 3-ASCL 2轴可能是Wnt信号传导的组成部分。因此，SMYD 3主要通过诱导ASCL 2来维持ASCL 2（+）CSC的自我更新和致瘤性。临床上，SMYD 3和ASCL 2的过表达与GC的恶性进展和不良患者结局相关。总之，这些发现定义了一种Wnt响应性CSC途径，可用于识别信号输出的基本调节因子，并揭示SMYD 3是消除人类癌症中CSC的表观遗传靶点。
Tumor growth is fueled by subset of cells with stem cell properties (Cancer stem cells, CSCs). While persistent activation of Wnt/beta-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 beta-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.