Continuous Zebularine Treatment Effectively Sustains Demethylation in Human Bladder Cancer Cells

Author:

Cheng Jonathan C.1,Weisenberger Daniel J.1,Gonzales Felicidad A.1,Liang Gangning1,Xu Guo-Liang2,Hu Ye-Guang2,Marquez Victor E.3,Jones Peter A.1

Affiliation:

1. Departments of Urology, Biochemistry, and Molecular Biology, USC/Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California

2. Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, People's Republic of China

3. Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute of Frederick, Frederick, Maryland

Abstract

ABSTRACT 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-(β- 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.

Publisher

American Society for Microbiology

Subject

Cell Biology,Molecular Biology

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