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Negative Regulation of Histone Deacetylase 8 Activity by Cyclic AMP-Dependent Protein Kinase A

H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612

Received 13 August 2003/ Returned for modification 23 September 2003/ Accepted 14 October 2003

Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl groups from lysine residues of histone and nonhistone proteins. Recent studies suggest that they are key regulators of many cellular events, including cell proliferation and cancer development. Human class I HDACs possess homology to the yeast RPD3 protein and include HDAC1, HDAC2, HDAC3, and HDAC8. While HDAC1, HDAC2, and HDAC3 have been characterized extensively, almost nothing is known about HDAC8. Here we report that HDAC8 is phosphorylated by cyclic AMP-dependent protein kinase A (PKA) in vitro and in vivo. The PKA phosphoacceptor site of HDAC8 is Ser³⁹, a nonconserved residue among class I HDACs. Mutation of Ser³⁹ to Ala enhances the deacetylase activity of HDAC8. In contrast, mutation of Ser³⁹ to Glu or induction of HDAC8 phosphorylation by forskolin, a potent activator of adenyl cyclase, decreases HDAC8's enzymatic activity. Remarkably, inhibition of HDAC8 activity by hyperphosphorylation leads to hyperacetylation of histones H3 and H4, suggesting that PKA-mediated phosphorylation of HDAC8 plays a central role in the overall acetylation status of histones.

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