In this report, we have further investigated the p53 regulation exerted by HIPK2 and highlighted a complex interplay between HIPK2, p300, Sirt1 and p53 connecting HIPK2-dependent Ser46 phosphorylation with Lys382 acetylation/deacetylation at which HIPK2 might fine-tune the apoptotic transcriptional activity of p53 in tumor cells subjected to genotoxic stress. This evidence concerns the gene TP53 and neoplasm.