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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2019-07-01
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Online Access: | https://doi.org/10.1177/2516865719865282 |
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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 |
work_keys_str_mv |
AT erinraho targetingwdr5awinninganticancerstrategy AT aprilmweissmiller targetingwdr5awinninganticancerstrategy AT stephenwfesik targetingwdr5awinninganticancerstrategy AT williamptansey targetingwdr5awinninganticancerstrategy |
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