Inhibition of histone methyltransferase G9a attenuates liver cancer initiation by sensitizing DNA-damaged hepatocytes to p53-induced apoptosis
Open Access
- 19 January 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 12 (1), 1-13
- https://doi.org/10.1038/s41419-020-03381-1
Abstract
While the significance of acquired genetic abnormalities in the initiation of hepatocellular carcinoma (HCC) has been established, the role of epigenetic modification remains unknown. Here we identified the pivotal role of histone methyltransferase G9a in the DNA damage-triggered initiation of HCC. Using liver-specific G9a-deficient (G9aΔHep) mice, we revealed that loss of G9a significantly attenuated liver tumor initiation caused by diethylnitrosamine (DEN). In addition, pharmacological inhibition of G9a attenuated the DEN-induced initiation of HCC. After treatment with DEN, while the induction of γH2AX and p53 were comparable in the G9aΔHep and wild-type livers, more apoptotic hepatocytes were detected in the G9aΔHep liver. Transcriptome analysis identified Bcl-G, a pro-apoptotic Bcl-2 family member, to be markedly upregulated in the G9aΔHep liver. In human cultured hepatoma cells, a G9a inhibitor, UNC0638, upregulated BCL-G expression and enhanced the apoptotic response after treatment with hydrogen peroxide or irradiation, suggesting an essential role of the G9a-Bcl-G axis in DNA damage response in hepatocytes. The proposed mechanism was that DNA damage stimuli recruited G9a to the p53-responsive element of the Bcl-G gene, resulting in the impaired enrichment of p53 to the region and the attenuation of Bcl-G expression. G9a deletion allowed the recruitment of p53 and upregulated Bcl-G expression. These results demonstrate that G9a allows DNA-damaged hepatocytes to escape p53-induced apoptosis by silencing Bcl-G, which may contribute to the tumor initiation. Therefore, G9a inhibition can be a novel preventive strategy for HCC.Keywords
Funding Information
- MEXT | Japan Society for the Promotion of Science (18K15741)
- Japan Agency for Medical Research and Development (JP17fk0210304, JP18fk0210040, JP19fk0210040, JP20fk0210040)
This publication has 50 references indexed in Scilit:
- Hepatocellular CarcinomaThe New England Journal of Medicine, 2019
- Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancerNature Genetics, 2016
- Histone methyltransferase SETDB1 regulates liver cancer cell growth through methylation of p53Nature Communications, 2015
- Trans-ancestry mutational landscape of hepatocellular carcinoma genomesNature Genetics, 2014
- Epigenetics in liver diseaseHepatology, 2014
- Histone lysine methyltransferase, suppressor of variegation 3-9 homolog 1, promotes hepatocellular carcinoma progression and is negatively regulated by microRNA-125bHepatology, 2012
- Cancer Epigenetics: From Mechanism to TherapyCell, 2012
- Enhancer of zeste homolog 2 epigenetically silences multiple tumor suppressor microRNAs to promote liver cancer metastasisHepatology, 2012
- Linking DNA methylation and histone modification: patterns and paradigmsNature Reviews Genetics, 2009
- G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesisGenes & Development, 2002