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J. Biol. Chem., Vol. 280, Issue 2, 1179-1185, January 14, 2005

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DNA Topoisomerase II Poison TAS-103 Transactivates GC-Box-dependent Transcription via Acetylation of Sp1^*

Takayuki Torigoe, Hiroto Izumi, Tetsuro Wakasugi, Ichiro Niina, Tomonori Igarashi, Takeshi Yoshida, Izumi Shibuya¶, Kazuo Chijiiwa||, Ken-ichi Matsuo**, Hideaki Itoh, and Kimitoshi Kohno

From the Department of Molecular Biology, the Department of Surgery 1 and the ^¶Department of Physiology I, University of Occupational and Environmental Health, School of Medicine, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka 807-8555, Japan, the ^||Department of Surgery 1, University of Miyazaki, Miyazaki-gun, Miyazaki 889-1692, Japan, and ^**Hanno Research Center, Taiho Pharmaceutical Co., Ltd., Hanno, Saitama 357-8527, Japan

Drug-induced modifications of transcription factors play important roles in both apoptosis and survival signaling. The data presented here show that the DNA topoisomerase II poison TAS-103 transactivated the SV40 promoter in a GC-box-dependent manner and induced Sp1 acetylation in cells expressing p300. This activity was not observed in cells lacking p300. TAS-103 treatment also enhanced the p300 content of the nucleus and the interaction of p300 with Sp1. Cellular susceptibility to TAS-103 was correlated with p300 expression but not with topoisomerase II expression. Furthermore, the presence of p300 significantly sensitized cancer cells to TAS-103 but not to cisplatin. Taken together, these findings demonstrate novel genomic responses to anticancer agents that modulate Sp1 acetylation and Sp1-dependent transcription in an apoptotic pathway.

Received for publication, September 13, 2004 , and in revised form, October 26, 2004.

^* This work was supported in part by the Ministry of Education, Culture, Sports, Science and Technology of Japan (Mext.), Kakenhi (Grant 13218132), an AstraZeneca Research Grant (2002), and a cancer research grant from Fukuoka Cancer Society. 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.

To whom correspondence should be addressed. Tel.: 81-93-691-7423; Fax: 81-93-692-2766; E-mail: k-kohno{at}med.uoeh-u.ac.jp.

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