Methylation Status of the Nanog Promoter Determines the Switch between Cancer Cells and Cancer Stem Cells
Methylation Status of the Nanog Promoter Determines the Switch between Cancer Cells and Cancer Stem Cells
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DOI：
10.1002/advs.201903035
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发表时间：
2020-01
期刊：
影响因子：
15.1
通讯作者：
Shupeng Liu;Kai Cheng;Hui Zhang;Ruijiao Kong;Shuo Wang;Chuanbin Mao;Shanrong Liu
中科院分区：
文献类型：
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作者：
Shupeng Liu;Kai Cheng;Hui Zhang;Ruijiao Kong;Shuo Wang;Chuanbin Mao;Shanrong Liu
肿瘤干细胞（CSCs）是肿瘤发生、转移和复发的主要原因。因此，干细胞被认为是癌症治疗的有希望的靶点。然而，由于其固有的可塑性和异质性，很难根除CSCs，并且非CSCs与CSCs之间转换的潜在机制尚不清楚。本研究表明miR - 135a与SMYD4联合激活Nanog表达，诱导非CSCs向CSCs转变。miR‐135a水平一旦升高，通过直接靶向DNMT1降低Nanog启动子中CG5位点的甲基化水平。SMYD4结合未甲基化的Nanog启动子，激活Nanog阴性肿瘤细胞中Nanog的表达。miR - 135a水平的体内调控可显著影响CSCs比例和肿瘤进展。这些发现表明，在miRNA‐135水平的控制下，Nanog启动子的DNA甲基化调节了非CSCs向CSCs的转换。此外，参与这些过程的相关通路miR - 135a/DNMT1和SMYD4是CSC靶向治疗的潜在靶点。
Cancer stem cells (CSCs) are the main cause of tumor development, metastasis, and relapse. CSCs are thus considered promising targets for cancer therapy. However, it is hard to eradicate CSCs due to their inherent plasticity and heterogeneity, and the underlying mechanism of the switch between non‐CSCs and CSCs remains unclear. Here, it is shown that miR‐135a combined with SMYD4 activates Nanog expression and induces the switch of non‐CSCs into CSCs. The miR‐135a level, once elevated, lowers the methylation level of the CG5 site in the Nanog promoter by directly targeting DNMT1. SMYD4 binds to the unmethylated Nanog promoter to activate Nanog expression in Nanog‐negative tumor cells. The in vivo regulation of miR‐135a levels could significantly affect both the CSCs proportion and tumor progression. These findings indicate that DNA methylation of the Nanog promoter modulates the switch of non‐CSCs into CSCs under the control of the miRNA‐135 level. In addition, the related pathways, miR‐135a/DNMT1 and SMYD4, involved in these processes are potential targets for CSC‐targeted therapy.