Senkyunolide A interrupts TRAF6-HDAC3 interaction to epigenetically suppress c-MYC and attenuate cholestatic liver injury
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PROVIDER: PRJNA1074384 | ENA |
REPOSITORIES: ENA
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Project description:Cholestatic liver diseases are highly prevalent and lack effective treatment, ultimately progressing to end-stage liver diseases. Our recent study indicates that the interplay between c-MYC and lncRNA H19 exacerbates the ductular reaction during cholestasis. However, the underlying mechanisms and their potential as therapeutic targets remain unclear. In this study, we demonstrate that senkyunolide A (SenA) effectively mitigates cholangiocyte hyperproliferation by epigenetically suppressing c-MYC expression and disrupting the downstream H19/Let-7a/Lin28a axis. Through comprehensive characterization using CHIP analysis, protein truncation, amino acid mutation or deletion, and the development of SenA derivatives, we identified a potential interaction between the carbonyl group in SenA and Arg483 in TRAF6, disrupting the TRAF6-HDAC3 complex. This dissociation facilitates the binding of HDAC3 to the MYC promoter region, resulting in enhanced histone deacetylation and transcriptional suppression. Here, we highlight the therapeutic potential of SenA in cholestatic liver diseases by elucidating its role in epigenetic regulation.
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Project description:Extrahepatic cholestasis leads to complex injury and repair processes that result in bile infarct formation, neutrophil infiltration, cholangiocyte and hepatocyte proliferation, extracellular matrix remodeling, and fibrosis. To identify early molecular mechanisms of injury and repair after bile duct obstruction, microarray analysis was performed on liver tissue 24 hours after bile duct ligation (BDL) or sham surgery. The most upregulated gene identified encodes plasminogen activator inhibitor 1 (PAI-1, Serpine 1), a protease inhibitor that blocks urokinase plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) activity. Because PAI-1, uPA, and tPA influence growth factor and cytokine processing as well as extracellular matrix remodeling, we evaluated the role of PAI-1 in cholestatic liver injury by comparing the injury and repair processes in wild-type (WT) and PAI-1-deficient (PAI-1-/-) mice after BDL. PAI-1-/- mice had fewer and smaller bile infarcts, less neutrophil infiltration, and higher levels of cholangiocyte and hepatocyte proliferation than WT animals after BDL. Furthermore, PAI-1-/- mice had higher levels of tPA activation and mature hepatocyte growth factor (HGF) after BDL than WT mice, suggesting that PAI-1 effects on HGF activation critically influence cholestatic liver injury. This was further supported by elevated levels of c-Met and Akt phosphorylation in PAI-1-/- mice after BDL. In conclusion, PAI-1 deficiency reduces liver injury after BDL in mice. These data suggest that inhibiting PAI-1 might attenuate liver injury in cholestatic liver diseases. Total RNA isolated using TRI Reagent (Sigma, St. Louis, MO) was purified with an RNeasy mini kit (Qiagen, Valencia, CA). Twenty micrograms cRNA was hybridized to a mouse GeneChip (U74Av2, Affymetrix, Santa Clara, CA) at the Siteman Cancer Center GeneChip facility as described by the manufacturer. Analyses used one mouse per chip. Gene expression changes were analyzed using Affymetrix MicroArray Suite 4.0 and GeneChip 3.1 Expression Analysis and Statistical Algorithms (Affymetrix). The complete methodology and full data sets for all 6 analyzed chips are available at http://bioinformatics.wustl.edu.beckerproxy.wustl.edu This study compares the injury and repair processed in wild-type mice after BDL.
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