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.
Cheng
Jonathan C
JC
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.
Yoo
Christine B
CB
Weisenberger
Daniel J
DJ
Chuang
Jody
J
Wozniak
Chandra
C
Liang
Gangning
G
Marquez
Victor E
VE
Greer
Sheldon
S
Orntoft
Torben F
TF
Thykjaer
Thomas
T
Jones
Peter A
PA
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