Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 51, Pages 15713-15718Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1522163112
Keywords
liver fibrosis; BET inhibitor; BRD4; hepatic stellate cell; antifibrotic therapy
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Funding
- NIH [DK057978, HL105278, DK090962, HL088093, ES010337, CA014195]
- National Health and Medical Research Council of Australia [512354, 632886]
- Leona M. and Harry B. Helmsley Charitable Trust [2012-PG-MED002]
- Samuel Waxman Cancer Research Foundation
- Ipsen/Biomeasure
- Stand Up to Cancer Dream Team Translational Cancer Research Grant
- program of the Entertainment Industry Foundation [SU2C-AACR-DT0509]
- [K01DK102867]
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Liver fibrosis is characterized by the persistent deposition of extra-cellular 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.
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