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J. Biol. Chem., Vol. 281, Issue 42, 31359-31368, October 20, 2006

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Suberoylanilide Hydroxamic Acid Induces Akt-mediated Phosphorylation of p300, Which Promotes Acetylation and Transcriptional Activation of RelA/p65^*

From the Department of Surgery, University of Virginia School of Medicine, Charlottesville, Virginia 22908

We have previously demonstrated that the transcription factor NF-B 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-B. Here we provide evidence that suberoylanilide hydroxamic acid stimulates NF-B 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 (pSer¹⁸³⁴), and site-directed mutant proteins, we find that suberoylanilide hydroxamic acid stimulates Akt activity, which is required to phosphorylate p300 at Ser¹⁸³⁴. Akt-mediated phosphorylation of p300 dramatically increases its acetyltransferase activity as measured by an increased acetylation of RelA/p65 at Lys³¹⁰, a modification that is required for full NF-B transcription. Importantly, coordinate activation of Akt/p300 pathway by suberoylanilide hydroxamic acid occurs at the chromatin level, resulting in recruitment of activated Akt (pSer⁴⁷³), p300 (pSer¹⁸³⁴), acetylated RelA/p65 (Lys³¹⁰), and RNA polymerase II to the NF-B-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-B transcription and cell survival through signaling pathways involving Akt and increased p300 acetyltransferase activity.

Received for publication, May 10, 2006 , and in revised form, July 14, 2006.

^* This research was supported in part by Grants K08 CA83920 (to D. R. J) and F32 CA101497 (to C. E. D.) from the NCI, National Institutes of Health and the American Association for Cancer Research (to D. R. J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this article.

² To whom correspondence should be addressed: Dept. of Surgery, Box 800679, University of Virginia, Charlottesville, VA 22908-0679. Tel.: 434-243-6443; Fax: 434-982-1026; E-mail: djones{at}virginia.edu.

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