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Hepatitis B virus X protein induces the histone H3 lysine 9 trimethylation on the promoter of p16 gene in hepatocarcinogenesis.
Exp Mol Pathol. 2015 Dec; 99(3):399-408.EM

Abstract

Our previous study showed hepatitis B virus X protein (HBx) suppresses the p16 expression in hepatocarcinogenesis. In this study we explored the relationship between HBx and trimethylation of H3K9 (H3K9me3), and elucidated the underlying mechanisms in HBx inducing the tumor suppressor p16 gene silence. SMMC-7721 and HepG2 hepatoma cell lines were transfected with HBx-expressing plasmid. Immunohistochemistry, Western blotting and real-time polymerase chain reaction, were performed to detect the expressions of HBx, H3K9me3, and jumonji domain-containing protein 2B (JMJd2B). H3K9me3 enrichment on the p16 promoter was measured by immunoprecipitation-PCR (ChIP-PCR) analyses, and 39 cases of hepatitis B virus (HBV) associated-hepatocellular carcinoma (HCC) and corresponding noncancerous liver tissues were also examined. We demonstrated that HBx was able to upregulate H3K9me3 and suppress JMJd2B mRNA and protein levels in SMMC-7721 and HepG2 hepatoma cell lines. JMJd2B, as a specific target of H3K9me3 for demethylation, was inversely correlated with the levels of H3K9me3 in SMMC-7721 (r=-0.666, P<0.05) and HepG2 cells (r=-0.625, P<0.05). The ChIP-PCR data indicated that HBx remarkably increased H3K9me3 on the p16 promoter region. Immunohistochemistry analysis showed that H3K9me3 expression in HBx positive HCC samples were significantly higher than that in HBx negative HCC tissues and were associated with decreased levels of JMJd2B expression. JMJd2B immunoreactivity was also remarkably inversed to that of HBx in HCC tissues (r=-0.630, P<0.05). Our results provide evidence that HBx is able to induce H3K9me3 on the p16 promoter via the decrease of demethylase JMJd2B expression and thus promote the repression of p16 gene expression to enhance hepatocarcinogenesis.

Authors+Show Affiliations

Department of Pathology, Shanghai Medical College, Fudan University, Shanghai 200032, China.Department of Pathology, Huashan Hospital, Fudan University, Shanghai 200040, China.Department of Pathology, Shanghai Medical College, Fudan University, Shanghai 200032, China.Department of Pathology, Shanghai Medical College, Fudan University, Shanghai 200032, China.Department of Pathology, Shanghai Medical College, Fudan University, Shanghai 200032, China. Electronic address: zhurongss@fudan.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

26341139

Citation

Wang, Di-Yi, et al. "Hepatitis B Virus X Protein Induces the Histone H3 Lysine 9 Trimethylation On the Promoter of P16 Gene in Hepatocarcinogenesis." Experimental and Molecular Pathology, vol. 99, no. 3, 2015, pp. 399-408.
Wang DY, Zou LP, Liu XJ, et al. Hepatitis B virus X protein induces the histone H3 lysine 9 trimethylation on the promoter of p16 gene in hepatocarcinogenesis. Exp Mol Pathol. 2015;99(3):399-408.
Wang, D. Y., Zou, L. P., Liu, X. J., Zhu, H. G., & Zhu, R. (2015). Hepatitis B virus X protein induces the histone H3 lysine 9 trimethylation on the promoter of p16 gene in hepatocarcinogenesis. Experimental and Molecular Pathology, 99(3), 399-408. https://doi.org/10.1016/j.yexmp.2015.08.020
Wang DY, et al. Hepatitis B Virus X Protein Induces the Histone H3 Lysine 9 Trimethylation On the Promoter of P16 Gene in Hepatocarcinogenesis. Exp Mol Pathol. 2015;99(3):399-408. PubMed PMID: 26341139.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hepatitis B virus X protein induces the histone H3 lysine 9 trimethylation on the promoter of p16 gene in hepatocarcinogenesis. AU - Wang,Di-Yi, AU - Zou,Li-Ping, AU - Liu,Xiao-Jia, AU - Zhu,Hong-Guang, AU - Zhu,Rong, Y1 - 2015/09/02/ PY - 2015/07/30/received PY - 2015/08/31/accepted PY - 2015/9/6/entrez PY - 2015/9/6/pubmed PY - 2016/4/23/medline KW - Hepatitis B virus X protein KW - Hepatocellular carcinoma KW - Histone H3 lysine 9 trimethylation KW - Jumonji domain-containing protein 2B KW - p16 gene SP - 399 EP - 408 JF - Experimental and molecular pathology JO - Exp. Mol. Pathol. VL - 99 IS - 3 N2 - Our previous study showed hepatitis B virus X protein (HBx) suppresses the p16 expression in hepatocarcinogenesis. In this study we explored the relationship between HBx and trimethylation of H3K9 (H3K9me3), and elucidated the underlying mechanisms in HBx inducing the tumor suppressor p16 gene silence. SMMC-7721 and HepG2 hepatoma cell lines were transfected with HBx-expressing plasmid. Immunohistochemistry, Western blotting and real-time polymerase chain reaction, were performed to detect the expressions of HBx, H3K9me3, and jumonji domain-containing protein 2B (JMJd2B). H3K9me3 enrichment on the p16 promoter was measured by immunoprecipitation-PCR (ChIP-PCR) analyses, and 39 cases of hepatitis B virus (HBV) associated-hepatocellular carcinoma (HCC) and corresponding noncancerous liver tissues were also examined. We demonstrated that HBx was able to upregulate H3K9me3 and suppress JMJd2B mRNA and protein levels in SMMC-7721 and HepG2 hepatoma cell lines. JMJd2B, as a specific target of H3K9me3 for demethylation, was inversely correlated with the levels of H3K9me3 in SMMC-7721 (r=-0.666, P<0.05) and HepG2 cells (r=-0.625, P<0.05). The ChIP-PCR data indicated that HBx remarkably increased H3K9me3 on the p16 promoter region. Immunohistochemistry analysis showed that H3K9me3 expression in HBx positive HCC samples were significantly higher than that in HBx negative HCC tissues and were associated with decreased levels of JMJd2B expression. JMJd2B immunoreactivity was also remarkably inversed to that of HBx in HCC tissues (r=-0.630, P<0.05). Our results provide evidence that HBx is able to induce H3K9me3 on the p16 promoter via the decrease of demethylase JMJd2B expression and thus promote the repression of p16 gene expression to enhance hepatocarcinogenesis. SN - 1096-0945 UR - https://www.unboundmedicine.com/medline/citation/26341139/Hepatitis_B_virus_X_protein_induces_the_histone_H3_lysine_9_trimethylation_on_the_promoter_of_p16_gene_in_hepatocarcinogenesis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-4800(15)00182-3 DB - PRIME DP - Unbound Medicine ER -