Inhibition of histone readers bromodomain extra-terminal proteins alleviates scleroderma fibrosis

Vichaikul, S.; Palisoc, P. J.; Ali, M.; Campbell, P. L.; Amin, M. A.; Ruth, J. H.; Rohraff, D. M.; Hervoso, J. L.; Fox, D. A.; Khanna, D.; Sawalha, A.; Tsou, P.-S.

doi:10.1101/2020.08.07.242198

bioRxiv · 10.1101/2020.08.07.242198

Inhibition of histone readers bromodomain extra-terminal proteins alleviates scleroderma fibrosis

Vichaikul, S.·Palisoc, P. J.·Ali, M.·Campbell, P. L.·Amin, M. A.·Ruth, J. H.·Rohraff, D. M.·Hervoso, J. L.·Fox, D. A.·Khanna, D.·Sawalha, A.·Tsou, P.-S.

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Abstract

Binding of the bromodomain and extra-terminal domain proteins (BETs) to acetylated histone residues is critical for gene transcription. This study sought to determine the anti-fibrotic 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 anti-fibrotic effects in an animal model of scleroderma and in patient-derived diffuse cutaneous (dc)SSc fibroblasts. Transcriptome analysis of JQ1-treated dcSSc fibroblasts revealed differentially expressed genes related to extracellular matrix, cell cycle, and calcium signaling. The anti-fibrotic effect of BRD4 inhibition was at least in part mediated by downregulation of Ca2+/calmodulin-dependent protein kinase II (CaMKII-) and reduction of intracellular calcium concentrations. These results suggest that targeting calcium pathways or BRD4 might be novel therapeutic approaches for progressive tissue fibrosis.

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Vichaikul, S., Palisoc, P. J., Ali, M., Campbell, P. L., Amin, M. A., Ruth, J. H., Rohraff, D. M., Hervoso, J. L., Fox, D. A., Khanna, D., Sawalha, A., Tsou, P.-S.. 2020-08-10. Inhibition of histone readers bromodomain extra-terminal proteins alleviates scleroderma fibrosis. https://doi.org/10.1101/2020.08.07.242198

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