Methylation Status of the Nanog Promoter Determines the Switch between Cancer Cells and Cancer Stem Cells

Advanced Science

Chuanbin Mao¹  Hui Zhang²  Kai Cheng²  Shanrong Liu²  Shuo Wang²  Ruijiao Kong³  Shupeng Liu⁴ 

[1] Department of Chemistry and Biochemistry Stephenson Life Sciences Research Center University of Oklahoma 101 Stephenson Parkway Norman OK 73019‐5300 USA;Department of Laboratory Diagnostics Changhai Hospital Second Military Medical University Shanghai 200433 China;Department of Laboratory Diagnostics Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine Shanghai 200081 China;Department of Obstetrics and Gynecology Shanghai Tenth People's Hospital Tongji University Shanghai 200072 China;

关键词: cancer stem cells;    methylation;    miRNA;    Nanog;    plasticity;   

DOI  :  10.1002/advs.201903035

来源: DOAJ

【 摘 要 】

Abstract 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.

【 授权许可】

Unknown