Depletion of embryonic stem cell signature by histone deacetylase inhibitor in NCCIT cells: involvement of Nanog suppression.
The embryonic stem cell-like gene expression signature has been shown to be associated with poorly differentiated aggressive human tumors and has attracted great attention as a potential target for future cancer therapies. Here, we investigate the potential of the embryonic stem cell signature as molecular target for the therapy and the strategy to suppress the embryonic stem cell signature. The core stemness gene Nanog is abnormally overexpressed in human embryonic carcinoma NCCIT cells showing gene expression profiles similar to embryonic stem cells. Down-regulation of the gene by either small interfering RNAs targeting Nanog or histone deacetylase inhibitor apicidin causes reversion of expression pattern of embryonic stem cell signature including Oct4, Sox2, and their target genes, leading to cell cycle arrest, inhibition of colony formation in soft agar, and induction of differentiation into all three germ layers. These effects are antagonized by reintroduction of Nanog. Interestingly, embryonic carcinoma cells (NCCIT, NTERA2, and P19) exhibit a higher sensitivity to apicidin in down-regulation of Nanog compared with embryonic stem cells. Furthermore, the down-regulation of Nanog expression by apicidin is mediated by a coordinated change in recruitment of epigenetic modulators and transcription factors to the promoter region. These findings indicate that overexpression of stemness gene Nanog in NCCIT cells is associated with maintaining stem cell-like phenotype and suggest that targeting Nanog might be an approach for improved therapy of poorly differentiated tumors.
You
Jueng Soo
JS
Department of Biochemistry and Molecular Biology, College of Pharmacy, Sungkyunkwan University, Suwon, Korea.
Kang
Jae Ku
JK
Seo
Dong-Wan
DW
Park
Jae Hyun
JH
Park
Jong Woo
JW
Lee
Jae Cheol
JC
Jeon
Yae Jee
YJ
Cho
Eun Jung
EJ
Han
Jeung-Whan
JW
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation / Q000187:drug effects; D054278:Embryonal Carcinoma Stem Cells / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D000071317:Nanog Homeobox Protein; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D056572:Histone Deacetylase Inhibitors; D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D010456:Peptides, Cyclic; D014157:Transcription Factors; C102351:apicidin