Induced epigenetic modifications of the promoter chromatin silence survivin and inhibit tumor growth.
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.
Ma
Ai-Niu
AN
King's Lab, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
Huang
Wei-Lin
WL
Wu
Zhong-Nan
ZN
Hu
Ji-Fan
JF
Li
Tao
T
Zhou
Xiang-Jun
XJ
Wang
Yong-Xiang
YX
D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008175:Lung Neoplasms / Q000235:genetics / Q000628:therapy*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000235:genetics / Q000627:therapeutic use*; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000627:therapeutic use*; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins; D000077022:Survivin
C117749:Birc5 protein, mouse; D002843:Chromatin; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C548733:SurKex; D000077022:Survivin