SMYD3 controls a Wnt-responsive epigenetic switch for ASCL2 activation and cancer stem cell maintenance. (28th August 2018)

• Record Type: Journal Article
• Authors: Wang, Tao; Wu, Hong; Liu, Sha; Lei, Zengjie; Qin, Zhongyi; Wen, Liangzhi; Liu, Kaijun; Wang, Xingwei; Guo, Yan; Liu, Qin; Liu, Lei; Wang, Jun; Lin, Li; Mao, Chengyi; Zhu, Xiangfeng; Xiao, Hualiang; Bian, Xiuwu; Chen, Dongfeng; Xu, Chuan; Wang, Bin
• Is Part Of: Cancer letters. Volume 430(2018)
• Page Start: 11
• Page End: 24
• Publication Date: 2018-08-28
• Subjects: Histone methyltransferase -- Tumor-initiating cells -- Wnt signaling -- Self-renewal -- Gastric carcinoma; CSC Cancer stem cells -- GC Gastric carcinoma -- TCF T-cell factor -- ASCL2 Achaete-scute homolog 2 -- SMYD3 SET and MYND domain containing 3 -- bHLH Basic helix-loop-helix -- TSS Transcription start site -- OS Overall survival -- MFS Metastasis-free survival; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.05.003
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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. Highlights: ASCL2 + cells are Wnt-responsive CSCs that rely on ASCL2 for self-renewal. SMYD3 dictates H3K4me3 status at the ASCL2 locus to promote ASCL2 expression. SMYD3 is transcriptionally activated by the Wnt/β-catenin signaling pathway. SMYD3-ASCL2 axis is critical for self-renewal and tumorigenicity of ASCL2 + CSCs. Overexpression of SMYD3 and ASCL2 are associated with poor prognosis in GC patients.