Open AccessMethylation Status of the Nanog Promoter Determines the Switch between Cancer Cells and Cancer Stem Cells
Author(s) -
Liu Shupeng,
Cheng Kai,
Zhang Hui,
Kong Ruijiao,
Wang Shuo,
Mao Chuanbin,
Liu Shanrong
Publication year - 2020
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.201903035
Subject(s) - homeobox protein nanog , cancer stem cell , cancer research , nanog homeobox protein , biology , cancer cell , methylation , cancer , dna methylation , metastasis , microrna , stem cell , microbiology and biotechnology , chemistry , embryonic stem cell , sox2 , induced pluripotent stem cell , genetics , gene expression , gene
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.