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

被引：142

作者：

Bolden, Jessica E. ^{[1
]}

Tasdemir, Nilgun ^{[1
,2
,3
]}

Dow, Lukas E. ^{[1
]}

van Es, Johan H. ^{[4
]}

Wilkinson, John E. ^{[5
]}

Zhao, Zhen ^{[1
]}

Clevers, Hans ^{[4
,6
]}

Lowe, Scott W. ^{[1
,7
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA

[2] Watson Sch Biol Sci, Cold Spring Harbor, NY 11724 USA

[3] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA

[4] Hubrecht Inst, KNAW, NL-3584 CT Utrecht, Netherlands

[5] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA

[6] Univ Med Ctr Utrecht, NL-3584 CT Utrecht, Netherlands

[7] Howard Hughes Med Inst, New York, NY 10065 USA

来源：

CELL REPORTS | 2014年 / 8卷 / 06期

基金：

英国医学研究理事会;

关键词：

RNA INTERFERENCE; GENE; MICE; BROMODOMAINS; CHROMATIN; TARGET; MYC; MAINTENANCE; EXPRESSION; CARCINOMA;

D O I：

10.1016/j.celrep.2014.08.025

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：1919 / 1929

页数：11

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