Death-Associated Protein 6 (Daxx) Alleviates Liver Fibrosis by Modulating Smad2 Acetylation
Sung-Min Kim,
Won-Hee Hur,
Byung-Yoon Kang,
Sung-Won Lee,
Pu-Reun Roh,
Dong-Jun Park,
Pil-Soo Sung,
Seung-Kew Yoon
Affiliations
Sung-Min Kim
The Catholic University Liver Research Centre, Department of Biomedicine & Health Sciences, POSTECH-Catholic Biomedical Engineering Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
Won-Hee Hur
The Catholic University Liver Research Centre, Department of Biomedicine & Health Sciences, POSTECH-Catholic Biomedical Engineering Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
Byung-Yoon Kang
The Catholic University Liver Research Centre, Department of Biomedicine & Health Sciences, POSTECH-Catholic Biomedical Engineering Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
Sung-Won Lee
The Catholic University Liver Research Centre, Department of Biomedicine & Health Sciences, POSTECH-Catholic Biomedical Engineering Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
Pu-Reun Roh
The Catholic University Liver Research Centre, Department of Biomedicine & Health Sciences, POSTECH-Catholic Biomedical Engineering Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
Dong-Jun Park
The Catholic University Liver Research Centre, Department of Biomedicine & Health Sciences, POSTECH-Catholic Biomedical Engineering Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
Pil-Soo Sung
The Catholic University Liver Research Centre, Department of Biomedicine & Health Sciences, POSTECH-Catholic Biomedical Engineering Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
Seung-Kew Yoon
The Catholic University Liver Research Centre, Department of Biomedicine & Health Sciences, POSTECH-Catholic Biomedical Engineering Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
Transforming growth factor-β (TGF-β) has been identified as an inducer of hepatocyte epithelial–mesenchymal transition (EMT), which triggers liver fibrosis. Death-associated protein 6 (Daxx) is known to be associated with the TGF-β-induced apoptotic pathway, but the function of Daxx in liver fibrosis remains unknown. This study aimed to elucidate the role of Daxx in liver fibrosis. We used liver fibrosis tissues from humans and mice to assess Daxx expression. EMT properties and TGF-β signaling pathway activation were investigated in the Daxx-overexpressing FL83B cell line. The therapeutic effect of Daxx was investigated in a mouse model of liver fibrosis by the hydrodynamic injection of plasmids. The expression of Daxx was markedly decreased in hepatocytes from fibrotic human and mouse livers, as well as in hepatocytes treated with TGF-β in vitro. The overexpression of Daxx inhibited the EMT process by interfering with the TGF-β-induced phosphorylation of Smad2. Coimmunoprecipitation analysis confirmed that Daxx reduced the transcriptional activity of Smad2 by binding to its MH1 domain and interfering with Smad2 acetylation. In addition, the therapeutic delivery of Daxx alleviated liver fibrosis in a thioacetamide-induced fibrosis mouse model. Overall, our results indicate that Daxx could be a potential therapeutic target to modulate fibrogenesis, as well as a useful biomarker for liver fibrosis.
