An intramolecular G-quadruplex structure formed in the human MET promoter region and its biological relevance.
An intramolecular G-quadruplex structure formed in the human MET promoter region and its biological relevance.
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人 MET 启动子区域形成的分子内 G-四链体结构及其生物学相关性。
DOI：
10.1002/mc.22330
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发表时间：
2016
影响因子：
4.6
通讯作者：
Guan Yifu
中科院分区：
文献类型：
--
作者：
Yan Jing;Zhao Xiaoyang;Liu Bo;Yuan Ying;Guan Yifu
先前的研究表明，许多原癌基因的启动子区域可以折叠成G -四联体，这可能参与基因的调控。生物信息学分析表明，在人类metpromoter的- 48 ~ - 26区域（命名为Pu23WT）存在一个富含G‐的序列。在本研究中，我们在体外生理条件下证明了Pu23WT采用分子内平行的G‐四重结构，并且阳离子卟啉TMPyP4增强了Pu23WT G‐四重结构的稳定性。为了更好地了解Pu23WT在met表达中的功能，我们对几种癌细胞进行了一系列分析。实验数据显示，TMPyP4可降低metin HepG2、BGC823和U87MG细胞的表达，导致细胞增殖抑制、G1期细胞周期阻滞和细胞迁移迟缓。ChIP分析结果表明，TMPyP4可能禁止Pu23WT G‐四重体与激活子Sp1结合，这可能是导致metgene转录抑制的机制之一。这是首次研究人类基因启动子的G四重结构及其在癌细胞中的功能。我们相信这种结构是抗癌治疗的潜在靶点。©2015 Wiley期刊公司
Previous studies have shown that promoter regions of many proto‐oncogenes can fold into G‐quadruplexes, which are potentially involved in the regulation of genes. Bioinformatics analysis suggested that there was a G‐rich sequence within −48 to −26 region of the humanMETpromoter (named Pu23WT). In this study, we proved that Pu23WT adopted an intramolecular parallel G‐quadruplex structure under physiological conditionsin vitro, and the cationic porphyrin TMPyP4 enhanced the stability of the Pu23WT G‐quadruplex. To better understand the functions of Pu23WT in theMETexpression, we performed a series of analysis on several cancer cells. Experimental data revealed that TMPyP4 treatment attenuated the expression ofMETin HepG2, BGC823, and U87MG cells, resulting in the cellular proliferation inhibition, G1 phase cell cycle arrest and cell migration retardation. ChIP assay results indicated that TMPyP4 probably prohibited the Pu23WT G‐quadruplex from binding to the activator Sp1, which could be one of the mechanisms that led to the transcription inhibition ofMETgene. It is the first study on the G‐quadruplex structure in the humanMETpromoter and its functions in cancer cells. We believe that this structure is a potential target for anticancer treatment. © 2015 Wiley Periodicals, Inc.