RRC ID 66057
Author Russell JO, Ko S, Saggi HS, Singh S, Poddar M, Shin D, Monga SP.
Title Bromodomain and Extraterminal (BET) Proteins Regulate Hepatocyte Proliferation in Hepatocyte-Driven Liver Regeneration.
Journal Am J Pathol
Abstract Bromodomain and extraterminal (BET) proteins recruit key components of basic transcriptional machinery to promote gene expression. Aberrant expression and mutations in BET genes have been identified in many malignancies. Small molecule inhibitors of BET proteins such as JQ1 have shown efficacy in preclinical cancer models, including affecting growth of hepatocellular carcinoma. BET proteins also regulate cell proliferation in nontumor settings. We recently showed that BET proteins regulate cholangiocyte-driven liver regeneration. Here, we studied the role of BET proteins in hepatocyte-driven liver regeneration in partial hepatectomy (PHx) and acetaminophen-induced liver injury models in mice and zebrafish. JQ1 was injected 2 or 16 hours after PHx in mice to determine effect on hepatic injury, regeneration, and signaling. Mice treated with JQ1 after PHx displayed increased liver injury and a near-complete inhibition of hepatocyte proliferation. Levels of Ccnd1 mRNA and Cyclin D1 protein were reduced in animals injected with JQ1 16 hours after PHx and were even further reduced in animals injected with JQ1 2 hours after PHx. JQ1-treated zebrafish larvae after acetaminophen-induced injury also displayed notably impaired hepatocyte proliferation. In both models, Wnt signaling was prominently suppressed by JQ1. Our results show that BET proteins regulate hepatocyte proliferation-driven liver regeneration, and Wnt signaling is particularly sensitive to BET protein inhibition.
Volume 188(6)
Pages 1389-1405
Published 2018-6-1
DOI 10.1016/j.ajpath.2018.02.006
PII S0002-9440(17)30773-3
PMID 29545201
PMC PMC5971221
MeSH Acetaminophen / toxicity Analgesics, Non-Narcotic / toxicity Animals Azepines / pharmacology* Cell Proliferation* Chemical and Drug Induced Liver Injury / drug therapy Chemical and Drug Induced Liver Injury / etiology Chemical and Drug Induced Liver Injury / metabolism Chemical and Drug Induced Liver Injury / pathology* Hep G2 Cells Hepatectomy / adverse effects Hepatocytes / cytology* Hepatocytes / drug effects Hepatocytes / physiology Humans Liver Regeneration* Male Mice Mice, Inbred C57BL Proteins / antagonists & inhibitors* Signal Transduction Triazoles / pharmacology* Zebrafish
IF 3.491
Zebrafish Tg(6xTcf/LefBS-miniP:d2EGFP) isi04