Abstract B53: Post-translational modification of p53 by HDAC inhibitors leads to selective assembly of transcriptional complexes at the p21 locus

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Abstract CG-1521 is a novel histone deacetylase (HDAC) inhibitor that stabilizes the acetylation of p53 at lysine 373, triggering G2/M phase arrest and apoptosis in LNCaP cells. This is in contrast to the well known HDAC inhibitor trichostatin A (TSA) which stabilizes the acetylation of lysine 382 on p53 and triggers G1/S phase arrest and senesence. The known p53 target gene, p21, contains two p53 response elements (RE) and 6 Sp1 binding sites in its promoter. Previous work in LNCaP cells indicates acetylated p53 isoform-modulated assembly of an active or inactive transcriptional complex at these p53REs in response to CG-1521 or TSA, respectively. Consistent with this finding, p21 mRNA levels were increased only upon treatment with CG-1521. Treatment with either HDAC inhibitor led to the upregulation of p21 protein levels, with a difference in the speed and duration of this increase. A second protein, p21B, coded within the exons and introns of the classical p21 protein, has been implicated in the apoptotic response, should the cellular DNA repair machinery fail to resolve a genomic insult. p21B appears to be controlled by a p53RE within the first intron of p21. This RE exhibits the same qualitative loading characteristics of the classical p21 p53RE in response to cellular stress and the acetylation state of p53, yet is temporally expressed later than p21. Using chromatin immunoprecipitation assays at narrow timepoints, we have determined the temporal loading characteristics of this region upon treatment with the HDAC inhibitors CG-1521 and TSA. Our results demonstrate a clear difference in the components of the basal transcriptional complex depending on the HDAC-stabilized acetylation state of p53. This indicates the acetylation state of the p53 protein is an important regulator of the cellular response to stress and suggests HDAC inhibitors may have an important role as cancer therapeutics beyond their traditional role in histone modification. Citation Information: Cancer Res 2009;69(23 Suppl):B53.