期刊
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
卷 393, 期 4, 页码 592-597出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2010.02.020
关键词
Survivin; Gene silencing; DNA methylation; Histone modifications; Epigenetics
资金
- Shanghai Science and Technology Administration [03JC14049, 03431 9209]
- Ministry of Science and Technology, China [2009CB521900]
Anti-apoptotic survivin is over-expressed in a variety of human carcinomas and is considered as a therapeutic target in cancers. Suppression of survivin mRNA by RNAi and anti-sense nucleotides has proved to be a powerful anti-tumor therapy in both animal models and human investigations. In this communication, we tested an alternative approach to silence survivin by knocking down its gene transcription through a short methylated oligonucleotide (SurKex) that is complementary to the survivin gene promoter. Treatment of NCI-H460 cells with SurKex significantly suppressed the production of survivin mRNA and its oncoprotein. DNA bisulfite sequencing showed that SurKex induced site-specific de novo CpG methylation in the complementary region of survivin promoter. Chromatin immunoprecipitation assay also demonstrated that SurKex induced histone hypermethylation at histone H3K9 and H3K27 as well as deacetylation of histone H4 in the same regulatory region. SurKex remarkably inhibited tumor growth in nude mice bearing xenograft tumors. This study demonstrates that the synthetic methylated oligonucleotide SurKex inhibits tumor growth by silencing the survivin gene using a mechanism of altering the epigenotype in the survivin promoter. Thus, targeted epigenetic modification in the gene promoter may offer a new general strategy to silence tumor-related genes in tumor therapy. (C) 2010 Elsevier Inc. All rights reserved.
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