Journal
FEBS JOURNAL
Volume 276, Issue 15, Pages 4197-4206Publisher
WILEY
DOI: 10.1111/j.1742-4658.2009.07128.x
Keywords
histone deacetylase 3 (HDAC3); histone deacetylase 4 (HDAC4); p16; senescence; ZBP-89
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Funding
- The National Basic Research Program of China [2005CB522404, 2006CB910506]
- Program for Changjiang Scholars and Innovative Research Team (PCSIRT) in Universities [IRT0519]
- National Natural Science Foundation of China [30800557, 30671184]
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The transcription factor ZBP-89 has been implicated in the induction of growth arrest and apoptosis. In this article, we demonstrate that ZBP-89 was able to restrain senescence in NCI-H460 human lung cancer cells, through epigenetically regulating p16(INK4a) expression. Specifically, our results indicate that knockdown of ZBP-89 by RNA interference stimulated cellular senescence in NCI-H460 cells, as judged by the senescence-associated beta-galactosidase activity assay and senescence-associated heterochromatin foci assay, and this process could be reversed by RNA interference-mediated p16(INK4a) silencing. We also show that histone deacetylase (HDAC) 3 and HDAC4 inhibited p16(INK4a) promoter activity in a dose-dependent manner. Furthermore, chromatin immunoprecipitation assays verified that HDAC3 was recruited to the p16(INK4a) promoter by ZBP-89 through an epigenetic mechanism involving histone acetylation modification. Moreover, immunofluorescence and coimmunoprecipitation assays revealed that ZBP-89 and HDAC3 formed a complex. These data suggest that ZBP-89 and HDAC3, but not HDAC4, can work coordinately to restrain cell senescence by downregulating p16(INK4a) expression through an epigenetic modification of histones.
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