5-Aza-2'-deoxycytidine induces cytotoxicity in BGC-823 cells via DNA             methyltransferase 1 and 3a independent of p53 status.
The DNA methylation inhibitor 5-aza-2'-deoxycytidine (5-Aza-CdR) has therapeutic             value for the treatment of cancer. However, the mechanism by which 5-Aza-CdR induces             antineoplastic activity is not clear. The efficacy of 5-Aza-CdR on the contribution             of gene reactivation by demethylation and enzyme-DNA adduct formation is an important             unresolved question. The aim of this study was to explore the mechanism of the             effect of 5-Aza-CdR on human gastric cancer growth. Human BGC-823 cells were treated             with different concentrations of 5-Aza-CdR for different durations. Cell viability,             DNA damage and gene expression were determined. The results showed that 5-Aza-CdR             at low concentrations induced inhibition of gastric cancer BGC-823 cell proliferation             as well as increased apoptosis caused by DNA damage. For the first time, we demonstrated             that 5-Aza-CdR-induced cytotoxicity against BGC-823 cells was predominantly regulated             via upregulation of DNA methyltransferase 1, 3a and partially via reactivation             of RUNX3, which was independent of p53 status and its ability to activate p21Waf1/Cip1             expression. To our knowledge, this is the first demonstration of p53-independent             5-Aza-CdR action on DNA methyltransferases and demethylation. These results strongly             provide the preclinical rationale for the clinical evaluation of 5-Aza-CdR to             improve patient outcome in gastric cancer.
Department of Geriatrics, Renmin Hospital of Wuhan University, Wuchang District, Wuhan 430060, PR China.
Juan
J
Liu
Yan
Y
Zhang
Yi-Shan
YS
Xie
Fu-Liang
FL
Wang
Li-Jun
LJ
Zhang
Tao
T
Deng
He-Sheng
HS
Luo
D017209:Apoptosis / Q000187:drug effects; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D050677:Core Binding Factor Alpha 3 Subunit / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D019175:DNA Methylation / Q000187:drug effects; D000090205:DNA Methyltransferase 3A; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C493956:CDKN1A protein, human; D050677:Core Binding Factor Alpha 3 Subunit; D050759:Cyclin-Dependent Kinase Inhibitor p21; C000717967:DNMT3A protein, human; C493729:Runx3 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000077209:Decitabine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D001374:Azacitidine