Inducible In Vivo Silencing of Brd4 Identifies Potential Toxicities of Sustained BET Protein Inhibition

BET family proteins are novel therapeutic targets for cancer and inflammation and represent the first chromatin readers against which small-molecule inhibitors have been developed. First-generation BET inhibitors have shown therapeutic efficacy in preclinical models, but the consequences of sustaine...

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Main Authors:	Bolden, Jessica E., Tasdemir, Nilgun, Dow, Lukas E., van Es, Johan H., Wilkinson, John E., Zhao, Zhen, Clevers, Hans, Lowe, Scott W.
Format:	Online
Language:	English
Published:	2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234106/

id	pubmed-4234106
recordtype	oai_dc
spelling	pubmed-42341062014-11-17 Inducible In Vivo Silencing of Brd4 Identifies Potential Toxicities of Sustained BET Protein Inhibition Bolden, Jessica E. Tasdemir, Nilgun Dow, Lukas E. van Es, Johan H. Wilkinson, John E. Zhao, Zhen Clevers, Hans Lowe, Scott W. Article BET family proteins are novel therapeutic targets for cancer and inflammation and represent the first chromatin readers against which small-molecule inhibitors have been developed. First-generation BET inhibitors have shown therapeutic efficacy in preclinical models, but the consequences of sustained BET protein inhibition in normal tissues remain poorly characterized. Using an inducible and reversible transgenic RNAi mouse model, we show that strong suppression of the BET protein Brd4 in adult animals has dramatic effects in multiple tissues. Brd4-depleted mice display reversible epidermal hyperplasia, alopecia, and decreased cellular diversity and stem cell depletion in the small intestine. Furthermore, Brd4-suppressed intestines are sensitive to organ stress and show impaired regeneration following irradiation, suggesting that concurrent Brd4 suppression and certain cytotoxic therapies may induce undesirable synergistic effects. These findings provide important insight into Brd4 function in normal tissues and, importantly, predict several potential outcomes associated with potent and sustained BET protein inhibition. 2014-09-18 2014-09-25 /pmc/articles/PMC4234106/ /pubmed/25242322 http://dx.doi.org/10.1016/j.celrep.2014.08.025 Text en ©2014 The Authors This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0).
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Bolden, Jessica E. Tasdemir, Nilgun Dow, Lukas E. van Es, Johan H. Wilkinson, John E. Zhao, Zhen Clevers, Hans Lowe, Scott W.
spellingShingle	Bolden, Jessica E. Tasdemir, Nilgun Dow, Lukas E. van Es, Johan H. Wilkinson, John E. Zhao, Zhen Clevers, Hans Lowe, Scott W. Inducible In Vivo Silencing of Brd4 Identifies Potential Toxicities of Sustained BET Protein Inhibition
author_facet	Bolden, Jessica E. Tasdemir, Nilgun Dow, Lukas E. van Es, Johan H. Wilkinson, John E. Zhao, Zhen Clevers, Hans Lowe, Scott W.
author_sort	Bolden, Jessica E.
title	Inducible In Vivo Silencing of Brd4 Identifies Potential Toxicities of Sustained BET Protein Inhibition
title_short	Inducible In Vivo Silencing of Brd4 Identifies Potential Toxicities of Sustained BET Protein Inhibition
title_full	Inducible In Vivo Silencing of Brd4 Identifies Potential Toxicities of Sustained BET Protein Inhibition
title_fullStr	Inducible In Vivo Silencing of Brd4 Identifies Potential Toxicities of Sustained BET Protein Inhibition
title_full_unstemmed	Inducible In Vivo Silencing of Brd4 Identifies Potential Toxicities of Sustained BET Protein Inhibition
title_sort	inducible in vivo silencing of brd4 identifies potential toxicities of sustained bet protein inhibition
description	BET family proteins are novel therapeutic targets for cancer and inflammation and represent the first chromatin readers against which small-molecule inhibitors have been developed. First-generation BET inhibitors have shown therapeutic efficacy in preclinical models, but the consequences of sustained BET protein inhibition in normal tissues remain poorly characterized. Using an inducible and reversible transgenic RNAi mouse model, we show that strong suppression of the BET protein Brd4 in adult animals has dramatic effects in multiple tissues. Brd4-depleted mice display reversible epidermal hyperplasia, alopecia, and decreased cellular diversity and stem cell depletion in the small intestine. Furthermore, Brd4-suppressed intestines are sensitive to organ stress and show impaired regeneration following irradiation, suggesting that concurrent Brd4 suppression and certain cytotoxic therapies may induce undesirable synergistic effects. These findings provide important insight into Brd4 function in normal tissues and, importantly, predict several potential outcomes associated with potent and sustained BET protein inhibition.
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234106/
_version_	1613157347434168320

Inducible In Vivo Silencing of Brd4 Identifies Potential Toxicities of Sustained BET Protein Inhibition

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