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Proc Natl Acad Sci U S A. 2015 Dec 22;112(51):15713-8. doi: 10.1073/pnas.1522163112. Epub 2015 Dec 7.

BRD4 is a novel therapeutic target for liver fibrosis.

Author information

1
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037;
2
Razzavi Newman Integrated Genomics and Bioinformatics Core, Salk Institute for Biological Studies, La Jolla, CA 92037;
3
Storr Liver Unit, Westmead Millennium Institute and University of Sydney, Westmead Hospital, Westmead, New South Wales 2145, Australia;
4
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037; evans@salk.edu downes@salk.edu.
5
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037; Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037 evans@salk.edu downes@salk.edu.

Abstract

Liver fibrosis is characterized by the persistent deposition of extracellular matrix components by hepatic stellate cell (HSC)-derived myofibroblasts. It is the histological manifestation of progressive, but reversible wound-healing processes. An unabated fibrotic response results in chronic liver disease and cirrhosis, a pathological precursor of hepatocellular carcinoma. We report here that JQ1, a small molecule inhibitor of bromodomain-containing protein 4 (BRD4), a member of bromodomain and extraterminal (BET) proteins, abrogate cytokine-induced activation of HSCs. Cistromic analyses reveal that BRD4 is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways, where BRD4 is colocalized with profibrotic transcription factors. Furthermore, we show that JQ1 is not only protective, but can reverse the fibrotic response in carbon tetrachloride-induced fibrosis in mouse models. Our results implicate that BRD4 can act as a global genomic regulator to direct the fibrotic response through its coordinated regulation of myofibroblast transcription. This suggests BRD4 as a potential therapeutic target for patients with fibrotic complications.

KEYWORDS:

BET inhibitor; BRD4; antifibrotic therapy; hepatic stellate cell; liver fibrosis

Comment in

PMID:
26644586
PMCID:
PMC4697417
DOI:
10.1073/pnas.1522163112
[Indexed for MEDLINE]
Free PMC Article

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