Targeting WDR5: A WINning Anti-Cancer Strategy?
Loading...
Date
2019-07-18
Journal Title
Journal ISSN
Volume Title
Publisher
EPIGENETICS INSIGHTS
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.
Description
Keywords
Cancer therapy, chromatin, epigenetic mechanisms, histone methylation, MYC, small molecule inhibitors, WDR5
Citation
Aho E.R., Weissmiller A.M., Fesik S.W., Tansey W.P.. Targeting WDR5: A WINning Anti-Cancer strategy. Epigenet Insights. 2019; 12:2516865719865282