title: Hepatitis B virus X protein overcomes stress-induced premature senescence by repressing p16(INK4a) expression via DNA methylation.
abstract: Cellular senescence is an important tumor suppression process under diverse oncogenic conditions, entering a state of irreversible growth arrest to prevent damaged cells from undergoing aberrant proliferation. Developing a means of evading senescence thus seems to be a fundamental task that all cancer cells should solve early on. Here, we show that an oncogenic X protein of hepatitis B virus (HBx) overcomes cellular senescence provoked by a universal premature senescence inducer, H(2)O(2), in human hepatoma cells, as demonstrated by impaired induction of senescence-associated biomarkers, including morphological change, G(1) arrest, and beta-galactosidase activity, in the presence of HBx. HBx induced DNA hypermethylation of p16(INK4a) promoter and subsequently interfered action of transcription factors like Ets1 and Ets2 activated by H(2)O(2) through the p38(MAPK) pathway, resulting in inhibition of its transcription. Down-regulation of p16(INK4a) expression by HBx subsequently led to activation of G(1)-CDKs, phosphorylation of Rb, activation of E2F1, and finally evasion from G(1) arrest induced by H(2)O(2). Levels of another senescence regulator, p21(waf1), however, were not affected by HBx under our senescence-inducing conditions. In addition, the potentials of HBx to inactivate Rb and subsequently inhibit cellular senescence almost completely disappeared when levels of p16(INK4a) were recovered either by exogenous complementation or inhibition of the promoter hypermethylation. To our knowledge, our present study represents the first report that an oncogenic virus evades cellular senescence through epigenetic down-regulation of p16(INK4a) expression.
authors: Department of Microbiology, Pusan National University, Busan, Republic of Korea.
authors: Ye-Jin
authors: YJ
authors: Kim
authors: Jin Kyu
authors: JK
authors: Jung
authors: Sun Young
authors: SY
authors: Lee
authors: Kyung Lib
authors: KL
authors: Jang
mesh_terms: D049109:Cell Proliferation; D016922:Cellular Senescence / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D018197:Hepatoblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D016877:Oxidants / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D016160:Retinoblastoma Protein / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D054334:Viral Regulatory and Accessory Proteins; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D016877:Oxidants; D016160:Retinoblastoma Protein; D015534:Trans-Activators; D014157:Transcription Factors; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D006861:Hydrogen Peroxide; D048051:p38 Mitogen-Activated Protein Kinases