Citations to this article
Citation Information: JCI Insight. 2022;7(9):e150871. https://doi.org/10.1172/jci.insight.150871.
Abstract
Binding of the bromodomain and extraterminal domain proteins (BETs) to acetylated histone residues is critical for gene transcription. We sought to determine the antifibrotic efficacy and potential mechanisms of BET inhibition in systemic sclerosis (SSc). Blockade of BETs was done using a pan-BET inhibitor, JQ1; BRD2 inhibitor, BIC1; or BRD4 inhibitors AZD5153 or ARV825. BET inhibition, specifically BRD4 blockade, showed antifibrotic effects in an animal model of SSc and in patient-derived diffuse cutaneous SSc (dcSSc) fibroblasts. Transcriptome analysis of JQ1-treated dcSSc fibroblasts revealed differentially expressed genes related to extracellular matrix, cell cycle, and calcium (Ca2+) signaling. The antifibrotic effect of BRD4 inhibition was mediated at least in part by downregulation of Ca2+/calmodulin–dependent protein kinase II α and reduction of intracellular Ca2+ concentrations. On the basis of these results, we propose targeting Ca2+ pathways or BRD4 as potentially novel therapeutic approaches for progressive tissue fibrosis.
Authors
Sirapa Vichaikul, Mikel Gurrea-Rubio, M. Asif Amin, Phillip L. Campbell, Qi Wu, Megan N. Mattichak, William D. Brodie, Pamela J. Palisoc, Mustafa Ali, Sei Muraoka, Jeffrey H. Ruth, Ellen N. Model, Dallas M. Rohraff, Jonatan L. Hervoso, Yang Mao-Draayer, David A. Fox, Dinesh Khanna, Amr H. Sawalha, Pei-Suen Tsou
Citations to this article (7)
| Title and authors | Publication | Year |
|---|---|---|
|
Targeting CD13/aminopeptidase N as a novel therapeutic approach for scleroderma fibrosis
Sei Muraoka, William Brodie, Megan Mattichak, Mikel Gurrea-Rubio, Neha Khanna, Hafsa Amin, M. Amin, Phillip Campbell, Yuzo Ikari, Caroline Foster, Sirapa Vichaikul, Ellen Model, Morgan O'mara, Steven Petrovski, Karly Kozicki, Mustafa Ali, Pamela Palisoc, Jonatan Hervoso, Jeffrey Ruth, Lam Tsoi, John Varga, Johann Gudjonsson, Dinesh Khanna, David A. Fox, Pei-Suen Tsou |
Arthritis & rheumatology (Hoboken, N.J.) | 2024 |
|
Noval advance of histone modification in inflammatory skin diseases and related treatment methods
Zhang L, Chai R, Tai Z, Miao F, Shi X, Chen Z, Zhu Q |
Frontiers in immunology | 2024 |
|
Bromodomain-Containing Protein 9 Regulates Signaling Pathways and Reprograms the Epigenome in Immortalized Human Uterine Fibroid Cells.
Yang Q, Vafaei S, Falahati A, Khosh A, Bariani MV, Omran MM, Bai T, Siblini H, Ali M, He C, Boyer TG, Al-Hendy A |
International journal of molecular sciences | 2024 |
|
TRPA1 as a potential factor and drug target in scleroderma: dermal fibrosis and alternative macrophage activation are attenuated in TRPA1-deficient mice in bleomycin-induced experimental model of scleroderma
Mäki-Opas I, Hämäläinen M, Moilanen E, Scotece M |
Arthritis Research & Therapy | 2023 |
|
The Epigenetic Regulator BRD4 is Required for Myofibroblast Differentiation of Knee Fibroblasts
Dudakovic A, Bayram B, Bettencourt JW, Limberg AK, Galvan ML, Carrasco ME, Stans B, Thaler R, Morrey ME, Sanchez-Sotelo J, Berry DJ, van Wijnen AJ, Abdel MP |
Journal of Cellular Biochemistry | 2023 |
|
Targeted protein degradation reveals BET bromodomains as the cellular target of Hedgehog pathway inhibitor-1
Bagka M, Choi H, Héritier M, Schwaemmle H, Pasquer QT, Braun SM, Scapozza L, Wu Y, Hoogendoorn S |
Nature Communications | 2023 |
|
Bromo- and Extra-Terminal Domain Inhibitors Induce Mitochondrial Stress in Pancreatic Ductal Adenocarcinoma
Rana M, Kansal RG, Bisunke B, Fang J, Shibata D, Bajwa A, Yang J, Glazer ES |
Molecular cancer therapeutics | 2023 |
