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

Johanna Grinat, Julian Heuberger (), Ramon Oliveira Vidal, Neha Goveas, Frauke Kosel, Antoni Berenguer-Llergo, Andrea Kranz, Annika Wulf-Goldenberg, Diana Behrens, Bálint Melcher, Sascha Sauer, Michael Vieth, Eduard Batlle, A. Francis Stewart and Walter Birchmeier ()
Additional contact information
Johanna Grinat: Cancer Research Program, Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Society
Julian Heuberger: Cancer Research Program, Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Society
Ramon Oliveira Vidal: Scientific Genomics Platforms, Max Delbrück Center for Molecular Medicine (BIMSB/BIH)
Neha Goveas: Technische Universität Dresden
Frauke Kosel: Cancer Research Program, Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Society
Antoni Berenguer-Llergo: The Barcelona Institute of Science and Technology
Andrea Kranz: Technische Universität Dresden
Annika Wulf-Goldenberg: Experimental Pharmacology & Oncology (EPO)
Diana Behrens: Experimental Pharmacology & Oncology (EPO)
Bálint Melcher: Institute for Pathology, Klinikum Bayreuth
Sascha Sauer: Scientific Genomics Platforms, Max Delbrück Center for Molecular Medicine (BIMSB/BIH)
Michael Vieth: Institute for Pathology, Klinikum Bayreuth
Eduard Batlle: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology
A. Francis Stewart: Technische Universität Dresden
Walter Birchmeier: Cancer Research Program, Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Society

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-20222-z

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