Hepatitis B virus X protein induces the histone H3 lysine 9 trimethylation on the promoter of p16 gene in hepatocarcinogenesis

Wang, Diyi; Zou, Li‐Ping; Liu, Xiaojia; Zhu, Hongguang; Zhu, Rong

doi:10.1016/j.yexmp.2015.08.020

Cited by 15 publications

(16 citation statements)

References 38 publications

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“…The expression of HBx was detected at 24 h, significantly increased at 48 h in both cell lines after transfection of HBx-expressing plasmid (Figure 2A). We found that HBx could increase H3K9me3 levels in both cell lines, consistent with our previous study [11]. Pearson analysis showed that H3K9me3 levels were significantly correlated with HBx protein expression (Figure 2A, r = 0.791, P < 0.05).…”

Section: Resultssupporting

confidence: 92%

“…In the present study, we used a ChIP-chip microarray, which enables the genome-wide identification of binding sites of transcription factors and chromatin regulators [12, 13], and examined the influence of HBx on H3K9me3 enrichment profiles on promoter regions to test the hypothesis that H3K9me3 was associated with the pathogenesis of HBV-associated HCC [10, 11]. We found that H3K9me3 immunoreactivity levels were remarkably correlated to those of HBx in HCC tissues, and HBx was able to upregulate H3K9me3 levels in hepatoma cell lines.…”

Section: Discussionmentioning

confidence: 99%

“…HBx-expressing plasmid (pcDNA3.1-Flag-HBx) and control plasmid (pcDNA3.1) sequences, and transient transfection have been described previously [10, 11, 34]. Every cell line was transfected with 0.5 μg/well of HBx-expressing plasmid or control plasmid for 48h in 96-well plates.…”

Section: Methodsmentioning

confidence: 99%

“…Cells were lysed, and protein was extracted as previously described [10, 11]. Protein lysate from each sample was separated electrophoretically in sodium dodecyl sulfatepolyacrylamide gel, and then transferred to polyvinylidene fluoride (PVDF) membranes.…”

Section: Methodsmentioning

confidence: 99%

“…Histone H3 lysine 9 trimethylation (H3K9me3) is associated with gene silencing and serves as mechanism to inactivate tumor suppressor genes in various cancers [7–9]. Our previous studies demonstrated that HBx could promote both H3K9 trimethylation and DNA hypermethylation on the p16 promoter in hepatocarcinogenesis [10, 11]. These findings implicated that HBx-mediated H3K9me3 might be involved in the tumor suppressor gene silencing in carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Hepatitis B virus X protein influences enrichment profiles of H3K9me3 on promoter regions in human hepatoma cell lines

Wang

Liu

et al. 2016

Oncotarget

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We previously showed that hepatitis B virus (HBV) X protein (HBx) could promote the trimethylation of histone H3 lysine 9 (H3K9me3) to repress tumor suppressor genes in hepatocellular carcinoma (HCC). In this work, we analyze 23,148 human promoters using ChIP-chip to determine the effects of HBx on H3K9me3 enrichments in hepatoma cells with transfection of HBx-expressing plasmid. Immunohistochemistry for HBx and H3K9me3 was performed in 21 cases of HBV-associated HCC tissues. We identified that H3K9me3 immunoreactivity was significantly correlated with HBx staining in HCC tissues. ChIP-chip data indicated that HBx remarkably altered promoter enrichments of H3K9me3 in hepatoma cells. We identified 25 gene promoters, whose H3K9me3 enrichments are significantly altered in hepatoma cells transfected HBx-expressing plasmid, including 19 gaining H3K9m3, and six losing this mark. Most of these genes have not been previously reported in HCC, and BTBD17, MIR6089, ZNF205-AS1 and ZP1 have not previously been linked to cancer; only two genes (DAB2IP and ZNF185) have been reported in HCC. Genomic analyses suggested that genes with the differential H3K9me3 enrichments function in diverse cellular pathways and many are involved in cancer development and progression.

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hepatitis B virus X protein influences enrichment profiles of H3K9me3 on promoter regions in human hepatoma cell lines

Wang

Liu

et al. 2016

Oncotarget

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HBV PreC interacts with SUV39H1 to induce viral replication by blocking the proteasomal degradation of viral polymerase

Hou,

Zhao,

Cai

et al. 2024

Journal of Medical Virology

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Hepatitis B e antigen (HBeAg) seropositivity during the natural history of chronic hepatitis B (CHB) is known to coincide with significant increases in serum and intrahepatic HBV DNA levels. However, the precise underlying mechanism remains unclear. In this study, we found that PreC (HBeAg precursor) genetic ablation leads to reduced viral replication both in vitro and in vivo. Furthermore, PreC impedes the proteasomal degradation of HBV polymerase, promoting viral replication. We discovered that PreC interacts with SUV39H1, a histone methyltransferase, resulting in a reduction in the expression of Cdt2, an adaptor protein of CRL4 E3 ligase targeting HBV polymerase. SUV39H1 induces H3K9 trimethylation of the Cdt2 promoter in a PreC‐induced manner. CRISPR‐mediated knockout of endogenous SUV39H1 or pharmaceutical inhibition of SUV39H1 decreases HBV loads in the mouse liver. Additionally, genetic depletion of Cdt2 in the mouse liver abrogates PreC‐related HBV replication. Interestingly, a negative correlation of intrahepatic Cdt2 with serum HBeAg and HBV DNA load was observed in CHB patient samples. Our study thus sheds light on the mechanistic role of PreC in inducing HBV replication and identifies potential therapeutic targets for HBV treatment.

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DNA and Histone Methylation in Liver Cancer

Arai

Yotani

Kanai

2017

DNA and Histone Methylation as Cancer Targets

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Hepatitis B virus X protein induces the histone H3 lysine 9 trimethylation on the promoter of p16 gene in hepatocarcinogenesis

Cited by 15 publications

References 38 publications

Hepatitis B virus X protein influences enrichment profiles of H3K9me3 on promoter regions in human hepatoma cell lines

Hepatitis B virus X protein influences enrichment profiles of H3K9me3 on promoter regions in human hepatoma cell lines

HBV PreC interacts with SUV39H1 to induce viral replication by blocking the proteasomal degradation of viral polymerase

DNA and Histone Methylation in Liver Cancer

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