The epigenetic regulator Mll1 is required for Wnt-driven intestinal tumorigenesis and cancer stemness
Grinat J, Heuberger J, Vidal RO, Goveas N, Kosel F, Berenguer-Llergo A, Kranz A, Wulf-Goldenberg A, Behrens D, Melcher B, Sauer S, Vieth M, Batlle E, Stewart AF, Birchmeier W (2020)
Publication Type: Journal article
Publication year: 2020
Journal
Book Volume: 11
Article Number: 6422
Journal Issue: 1
DOI: 10.1038/s41467-020-20222-z
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.
Authors with CRIS profile
Involved external institutions
Max-Delbrück-Centrum für Molekulare Medizin / Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch
Germany (DE)
Technische Universität Dresden
Germany (DE)
Institute for Research in Biomedicine / IRB Barcelona
Spain (ES)
Experimental Pharmacology & Oncology Berlin-Buch GmbH
Germany (DE)
Klinikum Bayreuth
Germany (DE)
Germany (DE)
Technische Universität Dresden
Germany (DE)
Institute for Research in Biomedicine / IRB Barcelona
Spain (ES)
Experimental Pharmacology & Oncology Berlin-Buch GmbH
Germany (DE)
Klinikum Bayreuth
Germany (DE)
How to cite
APA:
Grinat, J., Heuberger, J., Vidal, R.O., Goveas, N., Kosel, F., Berenguer-Llergo, A.,... Birchmeier, W. (2020). The epigenetic regulator Mll1 is required for Wnt-driven intestinal tumorigenesis and cancer stemness. Nature Communications, 11(1). https://doi.org/10.1038/s41467-020-20222-z
MLA:
Grinat, Johanna, et al. "The epigenetic regulator Mll1 is required for Wnt-driven intestinal tumorigenesis and cancer stemness." Nature Communications 11.1 (2020).
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