Long noncoding RNA NEAT1 suppresses hepatocyte proliferation in fulminant hepatic failure through increased recruitment of EZH2 to the LATS2 promoter region and promotion of H3K27me3 methylation

Exp Mol Med. 2020 Mar;52(3):461-472. doi: 10.1038/s12276-020-0387-z. Epub 2020 Mar 10.

Abstract

Fulminant hepatic failure (FHF) refers to the rapid development of severe acute liver injury with impaired synthetic function and encephalopathy in people with normal liver or well-compensated liver disease. This study aimed to investigate the function of long noncoding RNA (lncRNA) nuclear-enriched abundant transcript 1 (NEAT1) on the proliferation and apoptosis of hepatocytes in FHF. Our results revealed that lncRNA NEAT1 was upregulated in cell and animal models of FHF induced by D-galactosamine (D-GalN)/lipopolysaccharide (LPS). Overexpression of lncRNA NEAT1 resulted in elevated hepatocyte apoptosis and impaired large tumor-suppressor kinase 2 (LATS2) expression and proliferation. Functional analysis revealed that knockdown of lncRNA NEAT1 inhibited hepatocyte apoptosis and induced proliferation both in vitro and in vivo. RNA immunoprecipitation and chromatin immunoprecipitation assays demonstrated that lncRNA NEAT1 recruited enhancer of zeste homolog 2 (EZH2) to the LATS2 promoter and repressed LATS2 expression. Furthermore, ectopic expression of LATS2 increased proliferation and inhibited hepatocyte apoptosis by regulating the Hippo/Yes-associated protein (YAP) signaling pathway. Taken together, our findings indicate that lncRNA NEAT1 might serve as a novel target for FHF therapy due to its regulation of H3K27me3 methylation-dependent promotion of LATS2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Cell Line
  • Cell Proliferation / genetics*
  • Enhancer of Zeste Homolog 2 Protein / genetics*
  • HEK293 Cells
  • Hepatocytes / physiology*
  • Histones / genetics*
  • Humans
  • Liver Failure, Acute / genetics*
  • Male
  • Methylation
  • Promoter Regions, Genetic / genetics*
  • Protein-Serine-Threonine Kinases / genetics*
  • RNA, Long Noncoding / genetics*
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / genetics
  • Tumor Suppressor Proteins / genetics*

Substances

  • Histones
  • NEAT1 long non-coding RNA, human
  • RNA, Long Noncoding
  • Tumor Suppressor Proteins
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • LATS2 protein, human
  • Protein-Serine-Threonine Kinases