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Molecular and Cellular Biology, April 2006, p. 2782-2790, Vol. 26, No. 7
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.7.2782-2790.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Acetylation of p53 at Lysine 373/382 by the Histone Deacetylase Inhibitor Depsipeptide Induces Expression of p21Waf1/Cip1

Ying Zhao,1 Shaoli Lu,1 Lipeng Wu,1 Guolin Chai,1 Haiying Wang,1 Yingqi Chen,1 Jia Sun,1 Yu Yu,1 Wen Zhou,1 Quanhui Zheng,1 Mian Wu,2 Gregory A. Otterson,3 and Wei-Guo Zhu1*

Department of Biochemistry and Molecular Biology, Peking University Health Sciences Center, #38 Xueyuan Road, Beijing 100083, China,1 University of Science and Technology of China, Hefei, China,2 Division of Hematology/Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 432103

Received 3 October 2005/ Returned for modification 15 November 2005/ Accepted 12 January 2006

Generally, histone deacetylase (HDAC) inhibitor-induced p21Waf1/Cip1 expression is thought to be p53 independent. Here we found that an inhibitor of HDAC, depsipeptide (FR901228), but not trichostatin A (TSA), induces p21Waf1/Cip1 expression through both p53 and Sp1/Sp3 pathways in A549 cells (which retain wild-type p53). This is demonstrated by measuring relative luciferase activities of p21 promoter constructs with p53 or Sp1 binding site mutagenesis and was further confirmed by transfection of wild-type p53 into H1299 cells (p53 null). That p53 was acetylated after depsipeptide treatment was tested by sequential immunoprecipitation/Western immunoblot analysis with anti-acetylated lysines and anti-p53 antibodies. The acetylated p53 has a longer half-life due to a significant decrease in p53 ubiquitination. Further study using site-specific antiacetyllysine antibodies and transfection of mutated p53 vectors (K319/K320/K321R mutated and K373R/K382R mutations) into H1299 cells revealed that depsipeptide specifically induces p53 acetylation at K373/K382, but not at K320. As assayed by coimmunoprecipitation, the K373/K382 acetylation is accompanied by a recruitment of p300, but neither CREB-binding protein (CBP) nor p300/CBP-associated factor (PCAF), to the p53 C terminus. Furthermore, activity associated with the binding of the acetylated p53 at K373/K382 to the p21 promoter as well as p21Waf1/Cip1 expression is significantly increased after depsipeptide treatment, as tested by chromatin immunoprecipitations and Western blotting, respectively. In addition, p53 acetylation at K373/K382 is confirmed to be required for recruitment of p300 to the p21 promoter, and the depsipeptide-induced p53 acetylation at K373/K382 is unlikely to be dependent on p53 phosphorylation at Ser15, Ser20, and Ser392 sites. Our data suggest that p53 acetylation at K373/K382 plays an important role in depsipeptide-induced p21Waf1/Cip1 expression.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, Peking University Health Science Center, #38 Xueyuan Road, Beijing 100083, China. Phone: 86-10-82802235. Fax: 86-10-82805079. E-mail: zhuweiguo{at}bjmu.edu.cn.

Molecular and Cellular Biology, April 2006, p. 2782-2790, Vol. 26, No. 7
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.7.2782-2790.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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