The EZH2- H3K27me3-DNMT1 complex orchestrates epigenetic silencing of the wwc1 gene, a Hippo/YAP pathway upstream effector, in breast cancer epithelial cells
文献类型：期刊论文
| 作者 | Xiong Liu; Chun Li; Rendong Zhang; Wenjun Xiao; Xia Niu; Xia jun Ye; Zijia Li; Yu xian Guo; Junyu Tan; Yaochen LI |
| 刊名 | Cellular Signalling
 |
| 出版日期 | 2018 |
| 文献子类 | 期刊论文 |
| 英文摘要 | It is well known that epithelial-mesenchymal transition (EMT) can confer cancer cells with invasive and mi- gratory capabilities associated with distant metastasis. As a key upstream factor in the Hippo pathway, Kibra (wwc1 gene) has been shown to suppress EMT in breast cancer cells, and we have found that its expression is reduced or lost completely in both human breast cancer cell lines and clinical tissue samples, particularly in triple negative breast cancer (TNBC). Unfortunately, the molecular mechanisms underlying this progression- associated event remain to be elucidated. Epigenetic gene silencing is one of the most common causes of sup- pressed expression of tumor suppressor genes. Furthermore, recent studies have demonstrated that EZH2 can recruit DNA methyltransferases, resulting in DNA methylation and subsequent gene silencing in certain cir- cumstances. Thus, we hypothesized that there may exist a link between EZH2 and DNA methylation in asso- ciation with wwc1 silencing in breast cancer. To test this hypothesis, we performed bisulfite sequencing, shRNA, co-IP, ChIP, MeDIP and ChIP-qPCR. As expected, RG108 or 5-Aza treatment improved the wwc1 gene tran- scription and Kibra protein expression. Both bisulfite sequencing and MeDIP demonstrated higher CpG me- thylation of the wwc1 promoter the TNBC cells (MDA-MB-231) than in luminal breast cancer cells (MCF7). It is noteworthy that ChIP and co-IP assays showed that EZH2, H3K27me3 and DNMT1 are enriched at the wwc1 promoter, and there exist physiologically relevant protein-protein interactions between them. We also found that EZH2 knockdown leads to a partial increase in Kibra expression and a considerable reduction in H3K27 and DNMT1 trimethylation. Moreover, ChIP-qPCR revealed more DNA fragments containing the wwc1 promoter in MDA-MB-231 than in MCF7 cells after immunoprecipitation with EZH2, DNMT1 and H3K27me3 antibodies. Collectively, our results reveal crosstalk between H3K27me3 inhibition catalyzed by EZH2 and CpG island methylation mediated by DNMT1 within the wwc1 promoter, which synergistically silence wwc1 gene expression in TNBC. Based on these results, we conclude that EZH2 shows promise as a potential anti-tumor target. |
| URL标识 | 查看原文 |
| 语种 | 英语 |
| 源URL | [http://ir.siat.ac.cn:8080/handle/172644/13872]  |
| 专题 | 深圳先进技术研究院_脑所 |
| 推荐引用方式 GB/T 7714 | Xiong Liu,Chun Li,Rendong Zhang,et al. The EZH2- H3K27me3-DNMT1 complex orchestrates epigenetic silencing of the wwc1 gene, a Hippo/YAP pathway upstream effector, in breast cancer epithelial cells[J]. Cellular Signalling,2018. |
| APA | Xiong Liu.,Chun Li.,Rendong Zhang.,Wenjun Xiao.,Xia Niu.,...&Yaochen LI.(2018).The EZH2- H3K27me3-DNMT1 complex orchestrates epigenetic silencing of the wwc1 gene, a Hippo/YAP pathway upstream effector, in breast cancer epithelial cells.Cellular Signalling. |
| MLA | Xiong Liu,et al."The EZH2- H3K27me3-DNMT1 complex orchestrates epigenetic silencing of the wwc1 gene, a Hippo/YAP pathway upstream effector, in breast cancer epithelial cells".Cellular Signalling (2018). |
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来源：深圳先进技术研究院
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