The miR-455-3p/HDAC2 axis plays a pivotal role in the progression and reversal of liver fibrosis and is regulated by epigenetics.
Histone deacetylases (HDACs), especially HDAC2, play a role in alleviating liver fibrosis; however, the specific upstream regulation mechanism is unknown. Herein, TargetScan was used to predict the potential upstream targets of HDAC2, and the role of miR-455-3p was explored. The dual luciferase reporter assay showed that miR-455-3p binds to the 3' UTR of HDAC2 mRNA. Additionally, miR-455-3p was downregulated in the liver tissues of patients with cirrhosis and mice with liver fibrosis, as well as in primary HSCs isolated from fibrotic mouse livers and TGF-β-treated LX-2 cells. In contrast, it is highly expressed in the reversal stage of hepatic fibrosis and MDI-cultured LX-2 cells. Our functional analyses showed that miR-455-3p overexpression facilitated apoptosis and reduced the expression of pro-fibrotic markers and the proliferation of activated LX-2 cells. On the contrary, miR-455-3p inhibition converted inactivated LX-2 cells into activated, proliferative, fibrogenic cells. Interestingly, restoration of HDAC2 expression partially blocked the function of miR-455-3p. Downregulated miR-455-3p expression can be restored by DNA methyltransferases in activated LX-2 cells. Methylation-specific PCR, bisulfite sequencing PCR, and chromatin immunoprecipitation assays indicated that the methylation level of miR-455-3p promoter CpG islands was elevated in TGF-β-treated LX-2 cells and that miR-455-3p was downregulated in activated LX-2 cells by DNA hypermethylation, which is mediated by DNMT3b and DNMT1. In conclusion, miR-455-3p acts as a liver fibrosis suppressor by targeting HDAC2, and its deficiency further aggravates the reversal phase of fibrosis. Thus, the epigenetics mediated miR-455-3p/HDAC2 axis may serve as a novel potential therapeutic target for clinical treatment of hepatic fibrosis.
['You|Hongmei|H|', 'Wang|Ling|L|', 'Bu|Fangtian|F|', 'Meng|Hongwu|H|', 'Pan|Xueyin|X|', 'Li|Juanjuan|J|', 'Zhang|Yafei|Y|', 'Wang|Ao|A|', 'Yin|Nana|N|', 'Huang|Cheng|C|', 'Li|Jun|J|0000-0001-7541-752X']
D000818:Animals D017209:Apoptosis D002251:Carbon Tetrachloride D049109:Cell Proliferation D044127:Epigenesis, Genetic D005786:Gene Expression Regulation D055166:Hepatic Stellate Cells D056464:Histone Deacetylase 2 D006801:Humans D008103:Liver Cirrhosis D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D035683:MicroRNAs D015398:Signal Transduction
miR-455-3p HDAC2 liver fibrosis epigenetics HSCs