Targeting WDR5: A WINning Anti-Cancer Strategy?

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 W DR5- in teraction (WIN) site, have been proposed to selectively kil...

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Main Authors: Erin R Aho, April M Weissmiller, Stephen W Fesik, William P Tansey
Format: Article
Language:English
Published: SAGE Publishing 2019-07-01
Series:Epigenetics Insights
Online Access:https://doi.org/10.1177/2516865719865282
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spelling doaj-e6bb94402f344c8e85f3d21648db55dc2020-11-25T02:48:07ZengSAGE PublishingEpigenetics Insights2516-86572019-07-011210.1177/2516865719865282Targeting WDR5: A WINning Anti-Cancer Strategy?Erin R Aho0April M Weissmiller1Stephen W Fesik2William P Tansey3Department of Cell and Developmental Biology, School of Medicine, Vanderbilt University, Nashville, TN, USADepartment of Cell and Developmental Biology, School of Medicine, Vanderbilt University, Nashville, TN, USADepartment of Biochemistry, School of Medicine, Vanderbilt University, Nashville, TN, USADepartment of Cell and Developmental Biology, School of Medicine, Vanderbilt University, Nashville, TN, USAWDR5 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 W DR5- in teraction (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.https://doi.org/10.1177/2516865719865282
collection DOAJ
language English
format Article
sources DOAJ
author Erin R Aho
April M Weissmiller
Stephen W Fesik
William P Tansey
spellingShingle Erin R Aho
April M Weissmiller
Stephen W Fesik
William P Tansey
Targeting WDR5: A WINning Anti-Cancer Strategy?
Epigenetics Insights
author_facet Erin R Aho
April M Weissmiller
Stephen W Fesik
William P Tansey
author_sort Erin R Aho
title Targeting WDR5: A WINning Anti-Cancer Strategy?
title_short Targeting WDR5: A WINning Anti-Cancer Strategy?
title_full Targeting WDR5: A WINning Anti-Cancer Strategy?
title_fullStr Targeting WDR5: A WINning Anti-Cancer Strategy?
title_full_unstemmed Targeting WDR5: A WINning Anti-Cancer Strategy?
title_sort targeting wdr5: a winning anti-cancer strategy?
publisher SAGE Publishing
series Epigenetics Insights
issn 2516-8657
publishDate 2019-07-01
description 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 W DR5- in teraction (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.
url https://doi.org/10.1177/2516865719865282
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AT aprilmweissmiller targetingwdr5awinninganticancerstrategy
AT stephenwfesik targetingwdr5awinninganticancerstrategy
AT williamptansey targetingwdr5awinninganticancerstrategy
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