Death-Associated Protein 6 (Daxx) Alleviates Liver Fibrosis by Modulating Smad2 Acetylation

Autor: Pil-Soo Sung, Sung Min Kim, Byung-Yoon Kang, Wonhee Hur, Dong-Jun Park, Seung Kew Yoon, Sung Won Lee, Pu-Reun Roh
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Liver Cirrhosis
0301 basic medicine
Epithelial-Mesenchymal Transition
Transcription
Genetic
QH301-705.5
Smad2 Protein
Thioacetamide
epithelial–mesenchymal transition
Article
03 medical and health sciences
0302 clinical medicine
Death-associated protein 6
Protein Domains
Transforming Growth Factor beta
Fibrosis
medicine
Animals
Humans
Epithelial–mesenchymal transition
Phosphorylation
Biology (General)
liver fibrosis
Cell Nucleus
Chemistry
Acetylation
transforming growth factor-β
General Medicine
medicine.disease
Mice
Inbred C57BL
Disease Models
Animal
death-associated protein 6
HEK293 Cells
030104 developmental biology
medicine.anatomical_structure
Liver
Apoptosis
030220 oncology & carcinogenesis
Hepatocyte
Hepatocytes
Cancer research
Signal transduction
Co-Repressor Proteins
Smad2
Molecular Chaperones
Protein Binding
Signal Transduction
Transforming growth factor
Zdroj: Cells
Volume 10
Issue 7
Cells, Vol 10, Iss 1742, p 1742 (2021)
ISSN: 2073-4409
DOI: 10.3390/cells10071742
Popis: 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.
Databáze: OpenAIRE
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