title: Screening with a novel cell-based assay for TAZ activators identifies a compound that enhances myogenesis in C2C12 cells and facilitates muscle repair in a muscle injury model.
abstract: The transcriptional coactivator with a PDZ-binding motif (TAZ) cooperates with various transcriptional factors and plays various roles. Immortalized human mammalian epithelial MCF10A cells form spheres when TAZ is overexpressed and activated. We developed a cell-based assay using sphere formation by TAZ-expressing MCF10A cells as a readout to screen 18,458 chemical compounds for TAZ activators. Fifty compounds were obtained, and 47 were confirmed to activate the TAZ-dependent TEAD-responsive reporter activity in HEK293 cells. We used the derived subset of compounds as a TAZ activator candidate minilibrary and searched for compounds that promote myogenesis in mouse C2C12 myoblast cells. In this study, we focused on one compound, IBS008738. IBS008738 stabilizes TAZ, increases the unphosphorylated TAZ level, enhances the association of MyoD with the myogenin promoter, upregulates MyoD-dependent gene transcription, and competes with myostatin in C2C12 cells. TAZ knockdown verifies that the effect of IBS008738 depends on endogenous TAZ in C2C12 cells. IBS008738 facilitates muscle repair in cardiotoxin-induced muscle injury and prevents dexamethasone-induced muscle atrophy. Thus, this cell-based assay is useful to identify TAZ activators with a variety of cellular outputs. Our findings also support the idea that TAZ is a potential therapeutic target for muscle atrophy.
authors.affiliation: Department of Medical Biochemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Zeyu
authors.initials: Z
authors.lastname: Yang
authors.forename: Kentaro
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Aradhan
authors.initials: A
authors.lastname: Sarkar
authors.forename: Junichi
authors.initials: J
authors.lastname: Maruyama
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Iwasa
authors.forename: Yijun
authors.initials: Y
authors.lastname: Bao
authors.forename: Mari
authors.initials: M
authors.lastname: Ishigami-Yuasa
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ito
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kagechika
authors.forename: Shoji
authors.initials: S
authors.lastname: Hata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishina
authors.forename: Shinya
authors.initials: S
authors.lastname: Abe
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kitagawa
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hata
mesh_terms: D000818:Animals; D002460:Cell Line; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D047908:Intracellular Signaling Peptides and Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D024510:Muscle Development / Q000187:drug effects*; D009132:Muscles / Q000187:drug effects* / Q000293:injuries* / Q000473:pathology; D009133:Muscular Atrophy / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D017570:MyoD Protein / Q000378:metabolism; D032446:Myoblasts / Q000187:drug effects; D018008:Myogenin / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C000588695:IBS008738; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D017570:MyoD Protein; D018008:Myogenin; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human