Inducible in vivo silencing of Brd4 identifies potential toxicities of sustained BET protein inhibition Journal Article

   

Authors:	Bolden, J. E.; Tasdemir, N.; Dow, L. E.; van Es, J. H.; Wilkinson, J. E.; Zhao, Z.; Clevers, H.; Lowe, S. W.
Article Title:	Inducible in vivo silencing of Brd4 identifies potential toxicities of sustained BET protein inhibition
Abstract:	BET family proteins are novel therapeutic targets forcancer 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 strongsuppression of the BET protein Brd4 in adult animalshas 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.
Journal Title:	Cell Reports
Volume:	8
Issue:	6
ISSN:	2211-1247
Publisher:	Cell Press
Date Published:	2014-09-25
Start Page:	1919
End Page:	1929
Language:	English
DOI:	10.1016/j.celrep.2014.08.025
PROVIDER:	scopus
PUBMED:	25242322
PMCID:	PMC4234106
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84907419946&partnerID=40&md5=81b0bfab468abe755cc8571bfe2e04b3
Notes:	Export Date: 3 November 2014 -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/64125