SMYD3 controls a Wnt-responsive epigenetic switch for ASCL2 activation and cancer stem cell maintenance

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.