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The epigenetic regulator Mll1 is required for Wnt-driven intestinal tumorigenesis and cancer stemness
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The epigenetic regulator Mll1 is required for Wnt-driven intestinal tumorigenesis and cancer stemness
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Journal Article
The epigenetic regulator Mll1 is required for Wnt-driven intestinal tumorigenesis and cancer stemness
2020
Overview
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.
Intestinal cancer stem cells (CSC) are associated with colon cancer. Here, the authors show that Wnt/beta-catenin signalling in CSC requires the epigenetic regulator Mll1 to promote stemness and tumourigenesis in murine and human colon cancer models.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/89
/ 13/95
/ 14/19
/ 38/15
/ 38/39
/ 49/91
/ 64/60
/ 82/1
/ 82/29
/ Ablation
/ Adenoma
/ Animals
/ Colon
/ Colonic Neoplasms - genetics
/ Colonic Neoplasms - pathology
/ Gene Expression Regulation, Neoplastic
/ Histone-Lysine N-Methyltransferase - metabolism
/ Histones
/ Humanities and Social Sciences
/ Humans
/ Myeloid-Lymphoid Leukemia Protein - metabolism
/ Neoplastic Stem Cells - metabolism
/ Neoplastic Stem Cells - pathology
/ Polycomb Repressive Complex 2 - metabolism
/ Receptors, G-Protein-Coupled - metabolism
/ Science
/ Switches
/ Tumors
