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

Authors

  • J. Grinat
  • J. Heuberger
  • R. Vidal
  • N. Goveas
  • F. Kosel
  • A. Berenguer-Llergo
  • A. Kranz
  • A. Wulf-Goldenberg
  • D. Behrens
  • B. Melcher
  • S. Sauer
  • M. Vieth
  • E. Batlle
  • A. Stewart
  • W. Birchmeier

Journal

  • Nature Communications

Citation

  • Nat Commun 11 (1): 6422

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.


DOI

doi:10.1038/s41467-020-20222-z