p16^INK4a plays a key role in control of cell cycle progression by negatively regulating the CDK4/6 activity. It was shown that histone acetyltransferase p300 had a positive effect on the activation of p16^INK4a promoter, whereas, histone deacetylases HDAC3/4 counteracted the p300-mediated activation of p16^INK4a promoter, and decreased the p16^INK4a mRNA and protein levels. Chromatin immunoprecipitation (ChIP) tests revealed that the transfection of p300 reversed the hypoacetylation status of histones at the p16^INK4a promoter mediated by HDAC3/4. Moreover, the immunofluorescence study showed that the nucleo-cytoplasmic shuttling of HDAC4 may play an important role. Furthermore, Western blot and ChIP assays demonstrated that the HDAC inhibitor sodium butyrate (NaBu) enhanced p16^INK4a expression through inducing histone hyperacetylation. Based on these data, a hypothetical model was proposed for the involvement of reversible histone acetylation in transcriptional regulation of the p16^INK4a gene.