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| Item Type: | Article |
|---|---|
| Title: | The epigenetic regulator Mll1 is required for Wnt-driven intestinal tumorigenesis and cancer stemness |
| Creators Name: | Grinat, J., Heuberger, J., Vidal, R., Goveas, N., Kosel, F., Berenguer-Llergo, A., Kranz, A., Wulf-Goldenberg, A., Behrens, D., Melcher, B., Sauer, S., Vieth, M., Batlle, E., Stewart, A. and Birchmeier, W. |
| 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. |
| Keywords: | beta Catenin, Carcinogenesis, Cell Differentiation, Colonic Neoplasms, G-Protein-Coupled Receptors, Genetic Epigenesis, HEK293 Cells, Histone-Lysine N-Methyltransferase, Histones, Intestines, Lysine, Methylation, Myeloid-Lymphoid Leukemia Protein, Neoplastic Gene Expression Regulation, Neoplastic Stem Cells, Nude Mice, Polycomb Repressive Complex 2, Tumor Cell Line, Up-Regulation, Wnt Signaling Pathway, Animals, Mice |
| Source: | Nature Communications |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 11 |
| Number: | 1 |
| Page Range: | 6422 |
| Date: | 21 December 2020 |
| Official Publication: | https://doi.org/10.1038/s41467-020-20222-z |
| PubMed: | View item in PubMed |
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