The transcription factor ZBP-89 suppresses p16 expression through a histone modification mechanism to affect cell senescence.

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 p(16INK4a) 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.
Mesh Terms:
Apoptosis, Cell Aging, Cell Division, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p16, DNA-Binding Proteins, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Histones, Humans, Kinetics, Lung Neoplasms, Neoplasm Proteins, Transcription Factors, beta-Galactosidase
FEBS J.
Date: Aug. 01, 2009
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