Abstract
Wnt/β-catenin signaling is crucial for intestinal carcinogenesis and the maintenance of intestinal cancer stem cells. Here we identify the histone methyltransferase Mll1 as a regulator of Wnt-driven intestinal cancer. Mll1 is highly expressed in Lgr5+ stem cells and human colon carcinomas with increased nuclear β-catenin. High levels of MLL1 are associated with poor survival of colon cancer patients. The genetic ablation of Mll1 in mice prevents Wnt/β-catenin-driven adenoma formation from Lgr5+ intestinal stem cells. Ablation of Mll1 decreases the self-renewal of human colon cancer spheres and halts tumor growth of xenografts. Mll1 controls the expression of stem cell genes including the Wnt/β-catenin target gene Lgr5. Upon the loss of Mll1, histone methylation at the stem cell promoters switches from activating H3K4 tri-methylation to repressive H3K27 tri-methylation, indicating that Mll1 sustains stem cell gene expression by antagonizing gene silencing through polycomb repressive complex 2 (PRC2)-mediated H3K27 tri-methylation. Transcriptome profiling of Wnt-mutated intestinal tumor-initiating cells reveals that Mll1 regulates Gata4/6 transcription factors, known to sustain cancer stemness and to control goblet cell differentiation. Our results demonstrate that Mll1 is an essential epigenetic regulator of Wnt/β-catenin-induced intestinal tumorigenesis and cancer stemness.
Highlights
Wnt/β-catenin signaling is crucial for intestinal carcinogenesis and the maintenance of intestinal cancer stem cells
We used immunohistochemistry to assess the expression of the histone methyltransferase MLL1 in human colon cancer biopsies
The majority of tumors exhibited moderate to strong MLL1 expression, which was not associated to any particular tumor stage
Summary
Wnt/β-catenin signaling is crucial for intestinal carcinogenesis and the maintenance of intestinal cancer stem cells. Transcriptome profiling of Wnt-mutated intestinal tumor-initiating cells reveals that Mll[1] regulates Gata4/6 transcription factors, known to sustain cancer stemness and to control goblet cell differentiation. High Wnt/β-catenin signaling in the crypts induces Lgr[5] expression and is crucial for stem cell maintenance[17,18,19]. Oncogenic Wnt signaling activates a stem cell gene expression program in colon cancer cells and confers cancer stemness[20]. We identify the histone methyltransferase Mll[1] as an epigenetic regulator of human and mouse intestinal cancer stem cells and tumors. Mll[1] promotes β-catenin-induced intestinal stem cell expansion and tumorigenesis, and controls the selfrenewal of colon cancer stem cells. Cancer stem cells are depleted upon loss of Mll[1], which sustains oncogenic Wnt-induced stemness by antagonizing Polycomb Group (PcG)-mediated silencing of key stem cell genes
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