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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 |
| 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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