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

Autor/innen

  • 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

Quellenangabe

  • Cell Rep 26 (2): 415-428

Zusammenfassung

  • 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.


DOI

doi:10.1016/j.celrep.2018.12.059