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.

Wang T ，Wu H ，Liu S ，Lei Z ，Qin Z ，Wen L ，Liu K ，Wang X ，Guo Y ，Liu Q ，Liu L ，Wang J ，Lin L ，Mao C ，Zhu X ，Xiao H ，Bian X ，Chen D ，Xu C ，Wang B ... -  《-》

R-spondin1/Wnt-enhanced Ascl2 autoregulation controls the self-renewal of colorectal cancer progenitor cells.

Ye J ，Liu S ，Shang Y ，Chen H ，Wang R ... -  《-》

The epigenetic regulator Mll1 is required for Wnt-driven intestinal tumorigenesis and cancer stemness.

Grinat J ，Heuberger J ，Vidal RO ，Goveas N ，Kosel F ，Berenguer-Llergo A ，Kranz A ，Wulf-Goldenberg A ，Behrens D ，Melcher B ，Sauer S ，Vieth M ，Batlle E ，Stewart AF ，Birchmeier W ... -  《Nature Communications》

Wnt/β-catenin signalling maintains self-renewal and tumourigenicity of head and neck squamous cell carcinoma stem-like cells by activating Oct4.

Accumulating evidence suggests that a distinct subpopulation of cancer stem cells (CSCs) is responsible for tumour initiation and progression in head and neck squamous cell carcinoma (HNSCC). Wnt/β-catenin signalling is essential for stem cell regulation and tumourigenesis, but its molecular mechanism in HNSCC CSCs remains unknown. We investigated whether Wnt/β-catenin signalling regulates self-renewal and tumourigenicity of HNSCC stem-like cells in vitro and in vivo. Cytoplasmic/nuclear β-catenin, a major effector of Wnt/β-catenin signalling, was expressed in a subpopulation of tumour cells in primary HNSCC tissue but in none of normal head and neck tissues. Overexpression of β-catenin increased proliferation of HNSCC cells and induced dedifferentiation of these cells to cells with stem-like features. Knockdown of β-catenin in HNSCC stem-like cells blocked their self-renewal capacity, stemness-associated gene expression, chemoresistance, and in vivo tumourigenicity. Furthermore, β-catenin directly regulates Oct4 transcription in HNSCC stem-like cells. In addition, the effect of shRNA-mediated repression of β-catenin on CSC traits in HNSCC stem-like cells was reversed by overexpression of Oct4. In patients with HNSCC, higher levels of both cytoplasmic/nuclear β-catenin and Oct4 correlated with the worst prognosis. These results suggest inhibition of Wnt/β-catenin signalling as a novel therapeutic strategy for targeting HNSCC stem-like cells.

Lee SH ，Koo BS ，Kim JM ，Huang S ，Rho YS ，Bae WJ ，Kang HJ ，Kim YS ，Moon JH ，Lim YC ... -  《-》

KDM3 epigenetically controls tumorigenic potentials of human colorectal cancer stem cells through Wnt/β-catenin signalling.

Li J ，Yu B ，Deng P ，Cheng Y ，Yu Y ，Kevork K ，Ramadoss S ，Ding X ，Li X ，Wang CY ... -  《Nature Communications》