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 p16INK4a 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 β-galactosidase activity assay and senescence-associated heterochromatin foci assay, and this process could be reversed by RNA interference-mediated p16INK4a silencing. We also show that histone deacetylase (HDAC) 3 and HDAC4 inhibited p16INK4a promoter activity in a dose-dependent manner. Furthermore, chromatin immunoprecipitation assays verified that HDAC3 was recruited to the p16INK4a 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 p16INK4a expression through an epigenetic modification of histones. Structured digital abstract • MINT-7144512: HDAC4 (uniprotkb:P56524) physically interacts (MI:0914) with ZBP-89 (uniprotkb:Q9UQR1) by anti tag coimmunoprecipitation (MI:0007) • MINT-7144482, MINT-7144499: ZBP-89 (uniprotkb:Q9UQR1) physically interacts (MI:0914) with HDAC3 (uniprotkb:O15379) by anti tag coimmunoprecipitation (MI:0007) • MINT-7144469: ZBP-89 (uniprotkb:Q9UQR1) and HDAC3 (uniprotkb:O15379) colocalize (MI:0403) by fluorescence microscopy (MI:0416)