The Wnt-driven Mll1 epigenome regulates salivary gland and head and neck cancer
Authors
- Q. Zhu
- L. Fang
- J. Heuberger
- A. Kranz
- J. Schipper
- K. Scheckenbach
- R. Oliveira Vidal
- D.Y. Sunaga-Franze
- M. Müller
- A. Wulf-Goldenberg
- S. Sauer
- W. Birchmeier
Journal
- Cell Reports
Citation
- Cell Rep 26 (2): 415-428
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.