DNA Methyltransferase 3B Plays a Protective Role Against Hepatocarcinogenesis Caused by Chronic Inflammation Via Maintaining Mitochondrial Homeostasis

Overview

Journal Sci Rep

Specialty Science

Date 2020 Dec 5

PMID 33277576

Citations 3

Authors

Eriko Iguchi

Atsushi Takai

Haruhiko Takeda

Ken Kumagai

Soichi Arasawa

Yuji Eso

Takahiro Shimizu

Yoshihide Ueda

Hiroyuki Marusawa

Hiroshi Seno

Affiliations

Soon will be listed here.

Abstract

Most hepatocellular carcinomas (HCCs) develop on the basis of chronic hepatitis, but the mechanism of epigenetic regulation in inflammatory hepatocarcinogenesis has yet to be elucidated. Among de novo DNA methyltransferases (DNMTs), DNMT3B has lately been reported to act specifically on actively transcribed genes, suggesting the possibility that it plays a role in the pathogenesis of cancer. We confirmed that DNMT3B isoforms lacking its catalytic domain were highly expressed in HCCs compared with non-tumorous liver tissue. To elucidate the role of DNMT3B in hepatocarcinogenesis, we generated a genetically engineered mouse model with hepatocyte-specific Dnmt3b deletion. The liver of the Dnmt3b-deficient mice exhibited an exacerbation of thioacetamide-induced hepatitis, progression of liver fibrosis and a higher incidence of HCC compared with the liver of the control mice. Whole-genome bisulfite sequencing verified a lower CG methylation level in the Dnmt3b-deficient liver, demonstrating differentially methylated regions throughout the genome. Transcriptome analysis revealed decreased expression of genes related to oxidative phosphorylation in the Dnmt3b-deficient liver. Moreover, primary hepatocytes isolated from the Dnmt3b-deficient mice showed reduced mitochondrial respiratory capacity, leading to the enhancement of oxidative stress in the liver tissue. Our findings suggest the protective role of DNMT3B against chronic inflammation and HCC development via maintaining mitochondrial homeostasis.

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