Induction of apoptosis of non-small cell lung cancer by a methylated oligonucleotide targeting survivin gene.
Survivin overexpression is closely linked to lung oncogenesis. Silencing of survivin gene by molecular antagonists has shown promise as novel anticancer strategies. DNA methylation is a critical epigenetic modification that silences gene transcription. In this study, we used a new methylated oligonucleotide, which mediates sequence-specific DNA methylation in cell, as a strategic alternative to survivin-targeting treatment, and investigated its efficacy in suppressing survivin expression and the consequent apoptotic induction potential in NCI-H460 cells. SurKex1, a methylated sense oligonucleotide, was shown to reduce specifically survivin mRNA expression and induce cell apoptosis. In addition, it has been supposed that the methylated oligonucleotide exerts its effect of gene silencing through the activation of DNA methyltransferase (DNMT1), but the exact mechanism is still unknown. Our data suggest for the first time that the SurKex1 exerts its down-regulatory effects on survivin expression through the activation of DNMT1.
Li
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School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China. lihl@sjtu.edu.cn
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D017209:Apoptosis / Q000235:genetics*; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D000077209:Decitabine; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009841:Oligonucleotides / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D014162:Transfection
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009841:Oligonucleotides; D000077022:Survivin; D000077209:Decitabine; D015254:DNA Modification Methylases; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; D053148:Caspase 3; D001374:Azacitidine