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

Qiang Wang,Shu Liu,Yujun Zhao,Ke Cheng,Lian Liu,Yingzi Ming,Sheng Zhang

doi:10.1038/s12276-020-0387-z

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.

Highlights

Fulminant hepatic failure (FHF), known as acute liver failure, is a severe liver injury induced by a variety of stimuli, ranging from viruses, drugs, and alcohol to hereditary metabolic disorders[1]
LncRNA nuclearenriched abundant transcript 1 (NEAT1) was upregulated and large tumor-suppressor kinase 2 (LATS2) was downregulated in FHF A previous report showed that the expression of long noncoding RNA (lncRNA) NEAT1 was significantly increased in nonalcoholic fatty liver disease (NAFLD) models in vivo and in vitro, while downregulation of lncRNA NEAT1 alleviated NAFLD through the mammalian target of rapamycin/S6K1 signaling pathway[23]
These results suggested that D-GalN/LPS treatment could cause hepatocyte injury in FHF and induce the expression of lncRNA NEAT1 while blocking the expression of LATS2

Summary

Introduction

Fulminant hepatic failure (FHF), known as acute liver failure, is a severe liver injury induced by a variety of stimuli, ranging from viruses, drugs, and alcohol to hereditary metabolic disorders[1]. The lncRNA nuclearenriched abundant transcript 1 (NEAT1) was detected in primary hepatocytes isolated from fibrotic livers and identified as a regulator in the progression of liver fibrosis[7]. YAP and TAZ are major downstream effectors of the Hippo axis and participate in modulating the expression of genes that are vital for cell proliferation and survival[15]. Deregulation of the Hippo pathway, abnormal YAP hyperactivation, has been broadly documented in liver physiology and pathology[17]. The current study aims to elucidate the role and mechanism of action of lncRNA NEAT1 in apoptosis in D-GalN/LPSinduced FHF. We established cell and animal models of FHF by the administration of D-GalN/ LPS and evaluated various parameters, such as liver damage, hepatocyte apoptosis, and proliferation

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