BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells.

Autor:	Campbell AE; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA., Oliva J; Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University, Saint Louis, MO, 63104, USA., Yates MP; Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University, Saint Louis, MO, 63104, USA., Zhong JW; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA., Shadle SC; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.; Molecular and Cellular Biology Program, University of Washington, Seattle, WA, 98105, USA., Snider L; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA., Singh N; Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University, Saint Louis, MO, 63104, USA., Tai S; Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University, Saint Louis, MO, 63104, USA., Hiramuki Y; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA., Tawil R; Department of Neurology, University of Rochester Medical Center, Rochester, NY, 14642, USA., van der Maarel SM; Department of Human Genetics, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands., Tapscott SJ; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. stapscot@fredhutch.org.; Department of Neurology, University of Washington, Seattle, WA, 98105, USA. stapscot@fredhutch.org., Sverdrup FM; Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University, Saint Louis, MO, 63104, USA. fran.sverdrup@health.slu.edu.
Jazyk:	angličtina
Zdroj:	Skeletal muscle [Skelet Muscle] 2017 Sep 04; Vol. 7 (1), pp. 16. Date of Electronic Publication: 2017 Sep 04.
DOI:	10.1186/s13395-017-0134-x
Abstrakt:	Background: Facioscapulohumeral dystrophy (FSHD) is a progressive muscle disease caused by mutations that lead to epigenetic derepression and inappropriate transcription of the double homeobox 4 (DUX4) gene in skeletal muscle. Drugs that enhance the repression of DUX4 and prevent its expression in skeletal muscle cells therefore represent candidate therapies for FSHD. Methods: We screened an aggregated chemical library enriched for compounds with epigenetic activities and the Pharmakon 1600 library composed of compounds that have reached clinical testing to identify molecules that decrease DUX4 expression as monitored by the levels of DUX4 target genes in FSHD patient-derived skeletal muscle cell cultures. Results: Our screens identified several classes of molecules that include inhibitors of the bromodomain and extra-terminal (BET) family of proteins and agonists of the beta-2 adrenergic receptor. Further studies showed that compounds from these two classes suppress the expression of DUX4 messenger RNA (mRNA) by blocking the activity of bromodomain-containing protein 4 (BRD4) or by increasing cyclic adenosine monophosphate (cAMP) levels, respectively. Conclusions: These data uncover pathways involved in the regulation of DUX4 expression in somatic cells, provide potential candidate classes of compounds for FSHD therapeutic development, and create an important opportunity for mechanistic studies that may uncover additional therapeutic targets.
Databáze:	MEDLINE
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