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EZH2 as a Potential Target for NAFLD Therapy.

ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is a complex disease that is affected by genetic predisposition and epigenetic modification. Deregulation of epigenetic pathways is now recognized as a frequent event in NAFLD, and understanding the mechanistic roles of these epigenetic factors may lead to new strategies for NAFLD treatment. Enhancer of zeste homolog 2 (EZH2) catalyzes methylation on Lys 27 of histone H3, which leads to chromatin compaction and gene silencing. EZH2 regulates embryonic development and cell lineage determination and is related to many human diseases. Recent studies show that EZH2 has critical roles in liver development, homeostasis, and regeneration. Moreover, aberrant activation of EZH2 promotes NAFLD progression. Several EZH2 inhibitors have been developed and studied both in vitro and in clinical trials. In this review, we summarize our current understanding of the role of EZH2 in NAFLD and highlight its potential as a novel therapeutic target for NAFLD treatment.

SUBMITTER: Lim HJ

PROVIDER: S-EPMC7697020 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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EZH2 as a Potential Target for NAFLD Therapy.

Lim Hyun Jung HJ Kim Mirang M

International journal of molecular sciences 20201116 22

Non-alcoholic fatty liver disease (NAFLD) is a complex disease that is affected by genetic predisposition and epigenetic modification. Deregulation of epigenetic pathways is now recognized as a frequent event in NAFLD, and understanding the mechanistic roles of these epigenetic factors may lead to new strategies for NAFLD treatment. Enhancer of zeste homolog 2 (EZH2) catalyzes methylation on Lys 27 of histone H3, which leads to chromatin compaction and gene silencing. EZH2 regulates embryonic de ...[more]

PMID: 33207561

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Project description:Background: Non-alcoholic fatty liver disease (NAFLD) has gradually emerged as the most prevalent cause of chronic liver diseases. However, specific changes during the progression of NAFLD from non-fibrosis to advanced fibrosis and then hepatocellular carcinoma (HCC) are unresolved. Here, we firstly identify the key gene linking NAFLD fibrosis and HCC through analysis and experimental verification. Methods: Two GEO datasets (GSE89632, GSE49541) were performed for identifying differentially expressed genes (DEGs) associated with NAFLD progression from non-fibrosis to early fibrosis and eventually to advanced fibrosis. Subsequently, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analysis, protein-protein interaction (PPI) network were integrated to explore the potential function of the DEGs and hub genes. The expression of NUSAP1 was confirmed in vivo and in vitro NAFLD models at mRNA and protein level. Then, cell proliferation and migration under high fat conditions were verified by cell counting kit-8 (CCK-8) and wound-healing assays. The lipid content was measured with Oil Red O staining. Finally, the analysis of clinical survival curves was performed to reveal the prognostic value of the crucial genes among HCC patients via the online web-tool GEPIA2 and KM plotter. Results: 5510 DEGs associated with non-fibrosis NAFLD, 3913 DEGs about NAFLD fibrosis, and 739 DEGs related to NAFLD progression from mild fibrosis to advanced fibrosis were identified. Then, a total of 112 common DEGs were found. The result of enrichment analyses suggested that common DEGs were strongly associated with the glucocorticoid receptor pathway, regulation of transmembrane transporter activity, peroxisome, and proteoglycan biosynthetic process. Six genes, including KIAA0101, NUSAP1, UHRF1, RAD51AP1, KIF22, and ZWINT, were identified as crucial candidate genes via the PPI network. The expression of NUSAP1 was validated highly expressed in vitro and vivo NAFLD models at mRNA and protein level. NUSAP1 silence could inhibit the ability of cell proliferation, migration and lipid accumulation in vitro. Finally, we also found that NUSAP1 was significantly up-regulated at transcriptional and protein levels, and associated with poor survival and advanced tumor stage among HCC patients. Conclusion: NUSAP1 may be a potential therapeutic target for preventing NAFLD progression to liver cancer.

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EZH2 as a Potential Target for NAFLD Therapy.

Publications

EZH2 as a Potential Target for NAFLD Therapy.

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