Affiliation:
1. Department of Cell and Developmental Biology, School of Medicine, Vanderbilt University, Nashville, TN, USA
2. Department of Biochemistry, School of Medicine, Vanderbilt University, Nashville, TN, USA
Abstract
WDR5 is a component of multiple epigenetic regulatory complexes, including the mixed lineage leukemia (MLL)/SET complexes that deposit histone H3 lysine 4 methylation. Inhibitors of an arginine-binding cavity in WDR5, known as the WDR5-interaction (WIN) site, have been proposed to selectively kill MLL-rearranged malignancies via an epigenetic mechanism. We discovered potent WIN site inhibitors and found that they kill MLL cancer cells not through changes in histone methylation, but by displacing WDR5 from chromatin at protein synthesis genes, choking the translational capacity of these cells, and inducing death via a nucleolar stress response. The mechanism of action of WIN site inhibitors reveals new aspects of WDR5 function and forecasts broad therapeutic utility as anti-cancer agents.
Funder
national cancer institute
national institutes of health
robert j. kleberg, jr. and helen c. kleberg foundation
alex’s lemonade stand foundation for childhood cancer
edward p. evans foundation
rally foundation
american association for cancer research
Open Hands Overflowing Hearts co-funded research fellowship
Cited by
28 articles.
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