Preferential response of cancer cells to zebularine.
The frequent silencing of tumor suppressor genes by altered cytosine methylation and chromatin structural changes makes this process an attractive target for epigenetic therapy. Here we show that zebularine, a stable DNA cytosine methylation inhibitor, is preferentially incorporated into DNA and exhibits greater cell growth inhibition and gene expression in cancer cell lines compared to normal fibroblasts. In addition, zebularine preferentially depleted DNA methyltransferase 1 (DNMT1) and induced expression of cancer-related antigen genes in cancer cells relative to normal fibroblasts. Our results demonstrate that zebularine can be selective toward cancer cells and may hold clinical promise as an anticancer therapy.
USC/Norris Comprehensive Cancer Center, Departments of Urology, Biochemistry, and Molecular Biology, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90089, USA.
Jonathan C
JC
Cheng
Christine B
CB
Yoo
Daniel J
DJ
Weisenberger
Jody
J
Chuang
Chandra
C
Wozniak
Gangning
G
Liang
Victor E
VE
Marquez
Sheldon
S
Greer
Torben F
TF
Orntoft
Thomas
T
Thykjaer
Peter A
PA
Jones
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D003562:Cytidine / Q000031:analogs & derivatives; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D019942:Genes, p16; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D011741:Pyrimidine Nucleosides / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D011741:Pyrimidine Nucleosides; D003562:Cytidine; C009131:pyrimidin-2-one beta-ribofuranoside; D004248:DNA (Cytosine-5-)-Methyltransferases