KDM4C represses liver fibrosis by regulating H3K9me3 methylation of ALKBH5 and m6A methylation of snail1 mRNA.
J Dig Dis
; 25(5): 298-309, 2024 May.
Article
in En
| MEDLINE
| ID: mdl-38938016
ABSTRACT
OBJECTIVE:
We aimed to disclose the molecular mechanism of snail1 in liver fibrosis.METHODS:
Carbon tetrachloride (CCl4) was used to induce a liver fibrosis model in mice whereby serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were evaluated, and liver pathological alternations were assessed. Rat hepatic stellate cells (HSC-T6) were irritated with transforming growth factor (TGF)-ß1, followed by assessment of cell viability and migration. The levels of snail1, ALKBH5, and lysine specific demethylase 4C (KDM4C) were quantified by immunohistochemistry, western blot, or reverse transcription-quantitative polymerase chain reaction, in addition to α-smooth muscle actin (SMA), anti-collagen type I α1 (COL1A1), vimentin, and E-cadherin. Photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation and RNA stability were evaluated to determine the relationship between ALKBH5 and snail1. Changes in KDM4C-bound ALKBH5 promoter and enrichment of histone H3 lysine 9 trimethylation (H3K9me3) at the ALKBH5 promoter were determined using chromatin immunoprecipitation.RESULTS:
In fibrosis mice, snail1 was upregulated while ALKBH5 and KDM4C were downregulated. KDM4C overexpression reduced serum ALT and AST levels, liver injury, and α-SMA, COL1A1 and VIMENTIN expressions but increased E-cadherin expression. However, the aforementioned trends were reversed by concurrent overexpression of snail1. In HSC-T6 cells exposed to TGF-ß1, ALKBH5 overexpression weakened cell viability and migration, downregulated α-SMA, COL1A1 and VIMENTIN, upregulated E-CADHERIN, and decreased m6A modification of snail1 and its mRNA stability. KDM4C increased ALKBH5 expression by lowering H3K9me3 level, but inhibited HSC-T6 cell activation by regulating the ALKBH5/snail1 axis.CONCLUSION:
KDM4C decreases H3K9me3 methylation to upregulate ALKBH5 and subsequently inhibits snail1, ultimately impeding liver fibrosis.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Hepatic Stellate Cells
/
AlkB Homolog 5, RNA Demethylase
/
Snail Family Transcription Factors
/
Liver Cirrhosis
Limits:
Animals
Language:
En
Journal:
J Dig Dis
/
J. dig. dis
/
Journal of digestive diseases
Year:
2024
Document type:
Article
Affiliation country:
China
Country of publication:
Australia