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J. Biol. Chem., Vol. 279, Issue 15, 15161-15166, April 9, 2004

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5-Aza-2'-deoxycytidine Activates the p53/p21^Waf1/Cip1 Pathway to Inhibit Cell Proliferation^*

Wei-Guo Zhu¶, Theresa Hileman||, Yang Ke, Peichang Wang, Shaoli Lu, Wenrui Duan||, Zunyan Dai**, Tanjun Tong, Miguel A. Villalona-Calero||, Christoph Plass**, and Gregory A. Otterson||

From the Department of Biochemistry and Molecular Biology and the Cancer Research Center, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100083, China, the ^||Division of Hematology/Oncology, Department of Internal Medicine, and the ^**Division of Human Cancer Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210

In addition to its demethylating function, 5-aza-2'-deoxycytidine (5-aza-CdR) also plays an important role in inducing cell cycle arrest, differentiation, and cell death. However, the mechanism by which 5-aza-CdR induces antineoplastic activity is not clear. In this study, we found that 5-aza-CdR at limited concentrations (0.01–5 µM) induces inhibition of cell proliferation as well as increased p53/p21^Waf1/Cip1 expression in A549 cells (wild-type p53) but not in H1299 (p53-null) and H719 cells (p53 mutant). The p53-dependent p21^Waf1/Cip1 expression induced by 5-aza-CdR was not seen in A549 cells transfected with the wild-type human papilloma virus type-16 E6 gene that induces p53 degradation. Furthermore, deletion analysis and site-directed mutagenesis of the p21 promoter reveals that 5-aza-CdR induces p21^Waf1/Cip1 expression through two p53 binding sites in the p21 promoter. Finally, 5-aza-CdR-induced p21^Waf1/Cip1 expression was dependent on DNA damage but not on DNA demethylation as demonstrated by comet assay and bisulfite sequencing, respectively. Our data provide useful clues for judging the therapeutic efficacy of 5-aza-CdR in the treatment of human cancer cells.

Received for publication, October 24, 2003 , and in revised form, January 12, 2004.

^* This work was supported by 973 Plan Grant 2002CB713701 and National Natural and Scientific Foundation Grant 30371613, by a Peking University 985 Plan grant (to W.-G. Z.), by a Translational Research Grant from the Valvano Foundation (to G. A. O.), and by Grant P30CA16058 from the NCI, National Institutes of Health (Bethesda, MD). 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 may be addressed. E-mail: zhuweiguo{at}bjmu.edu.cn. To whom correspondence may be addressed. Tel.: 614-293-6786; Fax: 614-293-7529; E-mail: otterson-1{at}medctr.osu.edu.

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