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J. Biol. Chem., Vol. 283, Issue 36, 24420-24425, September 5, 2008

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Acetylation of PML Is Involved in Histone Deacetylase Inhibitor-mediated Apoptosis^*

Fumihiko Hayakawa¹, Akihiro Abe, Issay Kitabayashi, Pier Paolo Pandolfi^¶, and Tomoki Naoe

From the Department of Hematology and Oncology, Nagoya University, Graduate School of Medicine, Nagoya 466-8550, Japan, the Molecular Oncology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan, and the ^¶Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215

PML is a potent tumor suppressor and proapoptotic factor and is functionally regulated by post-translational modifications such as phosphorylation, sumoylation, and ubiquitination. Histone deacetylase (HDAC) inhibitors are a promising class of targeted anticancer agents and induce apoptosis in cancer cells by largely unknown mechanisms. We report here a novel post-transcriptional modification, acetylation, of PML. PML exists as an acetylated protein in HeLa cells, and its acetylation is enhanced by coexpression of p300 or treatment with a HDAC inhibitor, trichostatin A. Increased PML acetylation is associated with increased sumoylation of PML in vitro and in vivo. PML is involved in trichostatin A-induced apoptosis and PML with an acetylation-defective mutation shows an inability to mediate apoptosis, suggesting the importance of PML acetylation. Our work provides new insights into PML regulation by post-translational modification and new information about the therapeutic mechanism of HDAC inhibitors.

Received for publication, March 20, 2008 , and in revised form, July 7, 2008.

^* This work was supported by grants-in-aid from the Uehara Memorial Foundation, the National Institute of Biomedical Innovation, and the Ministry of Education, Culture, Sports, Science, and Technology of Japan. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1–S9 and supplemental data.

¹ To whom correspondence should be addressed: Dept. of Hematology and Oncology, Nagoya University, Graduate School of Medicine, 65 Tsurumaicho, Showa-ku, Nagoya, 466-8550, Japan. Fax: 81-52-744-2161; E-mail: bun-hy{at}med.nagoya-u.ac.jp.

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