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Cell Rep. 2019 Jan 8;26(2):415-428.e5. doi: 10.1016/j.celrep.2018.12.059.

The Wnt-Driven Mll1 Epigenome Regulates Salivary Gland and Head and Neck Cancer.

Author information

1
Cancer Research Program, Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Society, 13125 Berlin, Germany.
2
Cancer Research Program, Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Society, 13125 Berlin, Germany; Department of Biology, Southern University of Science and Technology (SUSTech), Shenzhen 518055, China; Medi-X Institute, SUSTech Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology (SUSTech), Shenzhen 518055, China.
3
Biotechnology Center, Technical University, 01307 Dresden, Germany.
4
Department of Head and Neck Surgery, Heinrich Heine University, 40225 Düsseldorf, Germany.
5
Systems Biology Program, Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Society, 13125 Berlin, Germany.
6
Experimental Pharmacology & Oncology (EPO), 13125 Berlin, Germany.
7
Cancer Research Program, Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Society, 13125 Berlin, Germany. Electronic address: wbirch@mdc-berlin.de.

Abstract

We identified a regulatory system that acts downstream of Wnt/β-catenin signaling in salivary gland and head and neck carcinomas. We show in a mouse tumor model of K14-Cre-induced Wnt/β-catenin gain-of-function and Bmpr1a loss-of-function mutations that tumor-propagating cells exhibit increased Mll1 activity and genome-wide increased H3K4 tri-methylation at promoters. Null mutations of Mll1 in tumor mice and in xenotransplanted human head and neck tumors resulted in loss of self-renewal of tumor-propagating cells and in block of tumor formation but did not alter normal tissue homeostasis. CRISPR/Cas9 mutagenesis and pharmacological interference of Mll1 at sequences that inhibit essential protein-protein interactions or the SET enzyme active site also blocked the self-renewal of mouse and human tumor-propagating cells. Our work provides strong genetic evidence for a crucial role of Mll1 in solid tumors. Moreover, inhibitors targeting specific Mll1 interactions might offer additional directions for therapies to treat these aggressive tumors.

KEYWORDS:

Axin2; ChIP-seq; H3K4me3 at promoters; SET domain; epigenetics; solid tumors; tumor-propagating cells

PMID:
30625324
DOI:
10.1016/j.celrep.2018.12.059
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