title: Inducible in vivo silencing of Brd4 identifies potential toxicities of sustained BET protein inhibition.
abstract: 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.
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Bolden
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Watson School of Biological Sciences, Cold Spring Harbor, NY 11724, USA; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Nilgun
authors.initials: N
authors.lastname: Tasdemir
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Lukas E
authors.initials: LE
authors.lastname: Dow
authors.affiliation: Hubrecht Institute/KNAW, Uppsalalaan 8, Utrecht 3584 CT, the Netherlands.
authors.forename: Johan H
authors.initials: JH
authors.lastname: van Es
authors.affiliation: Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Wilkinson
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Hubrecht Institute/KNAW, Uppsalalaan 8, Utrecht 3584 CT, the Netherlands; University Medical Center Utrecht, Uppsalalaan 8, Utrecht 3584 CT, the Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Howard Hughes Medical Institute, New York, NY 10065, USA. Electronic address: lowes@mskcc.org.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000378:metabolism; D002460:Cell Line; D004317:Doxorubicin / Q000633:toxicity; D005720:Gamma Rays; D006965:Hyperplasia / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D012867:Skin / Q000473:pathology; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D013950:Thymus Gland / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D004317:Doxorubicin; D035683:MicroRNAs; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C486694:Brd4 protein, mouse; D000092468:Bromodomain Containing Proteins; C493597:Lgr5 protein, mouse