Journal
CANCER LETTERS
Volume 288, Issue 2, Pages 226-235Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2009.07.007
Keywords
DNA methylation; Hepatitis B virus X; Cell senescence; P16(INK4a)
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Funding
- Korean Government [KRF-2007-313-C00545]
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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, H2O2, 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 p 16(INK4a) promoter and subsequently interfered action of transcription factors like Ets1 and Ets2 activated by H2O2 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 H2O2. 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. (C) 2009 Elsevier Ireland Ltd. All rights reserved.
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