The miR‐455‐3p/HDAC2 axis plays a pivotal role in the progression and reversal of liver fibrosis and is regulated by epigenetics

Abstract

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 3ʹ 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.