title: Suberoylanilide hydroxamic acid induces Akt-mediated phosphorylation of p300, which promotes acetylation and transcriptional activation of RelA/p65.
abstract: We have previously demonstrated that the transcription factor NF-kappaB is activated by histone deacetylase inhibitors in a PI3K/Akt-dependent manner. The molecular mechanisms governing this process have not been well described. By virtue of their inhibitory action, it is unclear whether the addition of histone deacetylase inhibitors simply preserves the acetylation status of RelA/p65 or whether they actively stimulate signaling cascades that result in increased acetylation and transcription of NF-kappaB. Here we provide evidence that suberoylanilide hydroxamic acid stimulates NF-kappaB transcription through a signaling cascade that involves activation of both the serine/threonine kinase Akt and the p300 acetyltransferase. Using newly developed phosphospecific antibodies to p300 (pSer(1834)), and site-directed mutant proteins, we find that suberoylanilide hydroxamic acid stimulates Akt activity, which is required to phosphorylate p300 at Ser(1834). Akt-mediated phosphorylation of p300 dramatically increases its acetyltransferase activity as measured by an increased acetylation of RelA/p65 at Lys(310), a modification that is required for full NF-kappaB transcription. Importantly, coordinate activation of Akt/p300 pathway by suberoylanilide hydroxamic acid occurs at the chromatin level, resulting in recruitment of activated Akt (pSer(473)), p300 (pSer(1834)), acetylated RelA/p65 (Lys(310)), and RNA polymerase II to the NF-kappaB-dependent cIAP-2 and Bfl-1/A1 promoters. These studies provide evidence that histone deacetylase inhibitors, such as suberoylanilide hydroxamic acid, not only inhibit deacetylase activity but also stimulate active NF-kappaB transcription and cell survival through signaling pathways involving Akt and increased p300 acetyltransferase activity.
authors.affiliation: Department of Surgery, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Chadrick E
authors.initials: CE
authors.lastname: Denlinger
authors.forename: Brian K
authors.initials: BK
authors.lastname: Rundall
authors.forename: Philip W
authors.initials: PW
authors.lastname: Smith
authors.forename: David R
authors.initials: DR
authors.lastname: Jones
mesh_terms: D017209:Apoptosis; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D017930:Genes, Reporter; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012694:Serine / Q000737:chemistry; D051996:Transcription Factor RelA / Q000378:metabolism*; D015533:Transcriptional Activation; D000077337:Vorinostat; D050880:p300-CBP Transcription Factors / Q000378:metabolism*
chemical_list: D006877:Hydroxamic Acids; C498143:RELA protein, human; D051996:Transcription Factor RelA; D012694:Serine; D000077337:Vorinostat; D050880:p300-CBP Transcription Factors; D051057:Proto-Oncogene Proteins c-akt