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The Wnt-driven Mll1 epigenome regulates salivary gland and head and neck cancer

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Item Type:Article
Title:The Wnt-driven Mll1 epigenome regulates salivary gland and head and neck cancer
Creators Name:Zhu, Q. and Fang, L. and Heuberger, J. and Kranz, A. and Schipper, J. and Scheckenbach, K. and Oliveira Vidal, R. and Sunaga-Franze, D.Y. and Müller, M. and Wulf-Goldenberg, A. and Sauer, S. and Birchmeier, W.
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:Tumor-Propagating Cells, Epigenetics, Solid Tumors, ChIP-seq, H3K4me3 at Promoters, SET Domain, Axin2, Animals, Mice
Source:Cell Reports
ISSN:2211-1247
Publisher:Cell Press / Elsevier (U.S.A.)
Volume:26
Number:2
Page Range:415-428
Date:8 January 2019
Official Publication:https://doi.org/10.1016/j.celrep.2018.12.059
PubMed:View item in PubMed

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