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Bromodomain and Extraterminal (BET) Proteins Regulate Hepatocyte Proliferation in Hepatocyte‐Driven Liver Regeneration
Author(s) -
Russell Jacquelyn Olivia,
Ko Sungjin,
Shin Donghun,
Monga Satdarshan Paul
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.531.7
Subject(s) - bromodomain , liver regeneration , epigenetics , hepatocyte , biology , liver injury , cancer research , cell growth , histone , microbiology and biotechnology , bet inhibitor , regeneration (biology) , biochemistry , gene , pharmacology , in vitro
Bromodomain and extraterminal (BET) proteins are epigenetic readers capable of binding to the acetylated lysine tails of histones, where they recruit key components of the basic transcriptional machinery to promote transcriptional activation of a wide variety of genes. Aberrant epigenetic gene regulation has been identified in many human malignancies, including genetic mutations in BET proteins. Excitingly, small molecule inhibitors of BET proteins, such as JQ1, have shown efficacy in preclinical models of various hematological and solid tumors without widespread toxicity to normal tissues. Importantly, JQ1 was shown to inhibit cell growth of hepatocellular carcinoma (HCC) cell lines. BET proteins have also been shown to regulate cell proliferation in non‐tumor settings. We recently showed BET proteins regulate biliary‐driven liver regeneration. Therefore, we sought to study the roles of BET proteins in other models of liver regeneration. Since two‐thirds partial hepatectomy (PHx) in rodents and acetaminophen (APAP)‐induced liver injury in both zebrafish and mice are well‐established models to study the mechanisms of hepatocyte proliferation, we set out to determine if JQ1 could inhibit liver regeneration by blocking hepatocyte proliferation in the PHx and APAP‐injury models. We injected mice with JQ1 either 2 or 16 hours post‐PHx in order to determine the kinetics of BET protein activation and harvested animals at approximately 45 hours post‐surgery, as hepatocyte proliferation in mice peaks around 36–48 hours post‐PHx. We demonstrate here that animals treated with JQ1 after PHx display notably increased liver injury with elevated transaminases and a near‐complete inhibition of hepatocyte proliferation. Treatment with JQ1 after sham surgery did not induce liver injury in mice. Levels of Cyclin D1 mRNA and protein were reduced in 16 hour post‐PHx JQ1 injected animals, and were even further reduced if JQ1 was injected 2 hours post‐PHx. Zebrafish larvae treated with JQ1 after APAP‐induced liver injury also displayed impaired hepatocyte proliferation. Therefore our results show that BET proteins regulate hepatocyte proliferation‐driven liver regeneration and establish a model to determine the mechanisms by which BET proteins promote hepatocyte proliferation. Support or Funding Information Funding was provided via the NIH CATER training grant T32 EB001026. Funding was additionally provided through the NIDDK via 5R01DK062277‐13. Support was provided by the Cellular & Molecular Pathology Graduate Program at the University of Pittsburgh.