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Molecular and Cellular Biology, February 2004, p. 1270-1278, Vol. 24, No. 3
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.3.1270-1278.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Continuous Zebularine Treatment Effectively Sustains Demethylation in Human Bladder Cancer Cells

Jonathan C. Cheng,1 Daniel J. Weisenberger,1 Felicidad A. Gonzales,1 Gangning Liang,1 Guo-Liang Xu,2 Ye-Guang Hu,2 Victor E. Marquez,3 and Peter A. Jones1*

Departments of Urology, Biochemistry, and Molecular Biology, USC/Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California,1 Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, People's Republic of China,2 Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute of Frederick, Frederick, Maryland3

Received 22 August 2003/ Returned for modification 24 September 2003/ Accepted 27 October 2003

During tumorigenesis, tumor suppressor and cancer-related genes are commonly silenced by aberrant DNA methylation in their promoter regions. Recently, we reported that zebularine [1-(ß-D-ribofuranosyl)-1,2-dihydropyrimidin-2-one] acts as an inhibitor of DNA methylation and exhibits chemical stability and minimal cytotoxicity both in vitro and in vivo. Here we show that continuous application of zebularine to T24 cells induces and maintains p16 gene expression and sustains demethylation of the 5' region for over 40 days, preventing remethylation. In addition, continuous zebularine treatment effectively and globally demethylated various hypermethylated regions, especially CpG-poor regions. The drug caused a complete depletion of extractable DNA methyltransferase 1 (DNMT1) and partial depletion of DNMT3a and DNMT3b3. Last, sequential treatment with 5-aza-2'-deoxycytidine followed by zebularine hindered the remethylation of the p16 5' region and gene resilencing, suggesting the possible combination use of both drugs as a potential anticancer regimen.

* Corresponding author. Mailing address: USC/Norris Comprehensive Cancer Center and Hospital, 1441 Eastlake Ave., Room 8302L, Mail Stop 83, Los Angeles, CA 90089-9181. Phone: (323) 865-0816. Fax: (323) 865-0102. E-mail: jones_p{at}ccnt.hsc.usc.edu.

Molecular and Cellular Biology, February 2004, p. 1270-1278, Vol. 24, No. 3
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.3.1270-1278.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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