CTCF公司
生物
染色质免疫沉淀
神经母细胞瘤
转录因子
癌症研究
长非编码RNA
染色质
下调和上调
电泳迁移率测定
微阵列分析技术
核糖核酸
RNA结合蛋白
转录调控
发起人
分子生物学
基因表达
基因
遗传学
细胞培养
增强子
作者
Xiaoli Zhao,D Li,Jiarui Pu,Ming Hong,Dehua Yang,Xuenan Xuan,Hongxia Qu,Kai Huang,Liduan Zheng,Qiangsong Tong
出处
期刊:Oncogene
[Springer Nature]
日期:2015-11-09
卷期号:35 (27): 3565-3576
被引量:69
摘要
Previous studies have indicated the important roles of MYCN in tumorigenesis and progression of neuroblastoma (NB), the most common extracranial solid tumor derived from neural crest in childhood. However, the regulatory mechanisms of MYCN expression in NB still remain largely unknown. In this study, through mining public microarray databases and analyzing the cis-regulatory elements and chromatin immunoprecipitation data sets, we identified CCCTC-binding factor (CTCF) as a crucial transcription factor facilitating the MYCN expression in NB. RNA immunoprecipitation, RNA electrophoretic mobility shift assay, RNA pull down and in vitro binding assay indicated the physical interaction between CTCF and MYCN opposite strand (MYCNOS), a natural noncoding RNA surrounding the MYNC promoter. Gain- and loss-of-function studies revealed that MYCNOS facilitated the recruitment of CTCF to its binding sites within the MYCN promoter to induce chromatin remodeling, resulting in enhanced MYCN levels and altered downstream gene expression, in cultured NB cell lines. CTCF cooperated with MYCNOS to suppress the differentiation and promote the growth, invasion and metastasis of NB cells in vitro and in vivo. In clinical NB tissues and cell lines, CTCF and MYCNOS were upregulated and positively correlated with MYCN expression. CTCF was an independent prognostic factor for unfavorable outcome of NB, and patients with high MYCNOS expression had lower survival probability. Taken together, these results demonstrate that CTCF cooperates with noncoding RNA MYCNOS to exhibit oncogenic activity that affects the aggressiveness and progression of NB through transcriptional upregulation of MYCN.
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