5-Aza-2′-deoxycytidine advances the epithelial-mesenchymal transition of breast cancer cells by demethylating Sipa1 promoter-proximal elements
5-Aza-2′-deoxycytidine advances the epithelial-mesenchymal transition of breast cancer cells by demethylating Sipa1 promoter-proximal elements
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5-Aza-2'-deoxycytidine 通过使 Sipa1 启动子近端元件去甲基化来促进乳腺癌细胞的 EMT。
DOI：
10.1242/jcs.236125
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发表时间：
2020-05-01
影响因子：
4
通讯作者：
Su, Li
中科院分区：
文献类型：
--
作者：
Lu, Ang;Wang, Wei;Su, Li
人乳腺癌细胞在调节转移转录组网络的基因组DNA CpGs的甲基化状态方面表现出相当大的多样性。在这项研究中，我们发现了人类Sipa1启动子-近端元件包含一个CpG岛，并证明了CpG岛的甲基化状态与Sipa1蛋白在癌细胞中的表达呈负相关。DNA甲基转移酶抑制剂5-Aza-2′-脱氧胞苷（5-Aza-CdR）在Sipa1低表达的MCF7乳腺癌细胞中促进Sipa1的表达。相反，在SIPA1高表达的MDA-MB-231乳腺癌细胞中，CpG岛的高甲基化会负向调节SIPA1的转录。此外，在MDA-MB-231细胞中敲除Sipa1后，上皮-间质转化（EMT）被逆转。然而，在SIPA1过表达或5-Aza-CdR处理的MCF7细胞中，EMT被促进。综上所述，Sipa1启动子-近端元件CpG岛的低甲基化可以增强Sipa1在乳腺癌细胞中的表达，从而促进癌细胞的EMTof，可能增加5-Aza-CdR治疗个体的癌细胞转移风险。
Human breast cancer cells exhibit considerable diversity in the methylation status of genomic DNA CpGs that regulate metastatic transcriptome networks. In this study, we identified human Sipa1 promoter-proximal elements that contained a CpG island and demonstrated that the methylation status of the CpG island was inversely correlated with SIPA1 protein expression in cancer cells. 5-Aza-2'-deoxycytidine (5-Aza-CdR), a DNA methyltransferase inhibitor, promoted the expression of Sipa1 in the MCF7 breast cancer cells with a low level of SIPA1 expression. On the contrary, in MDA-MB-231 breast cancer cells with high SIPA1 expression levels, hypermethylation of the CpG island negatively regulated the transcription of Sipa1. In addition, the epithelial-mesenchymal transition (EMT) was reversed after knocking down Sipa1 in MDA-MB-231 cells. However, the EMT was promoted in MCF7 cells with over-expression of SIPA1 or treated with 5-Aza-CdR. Taken together, hypomethylation of the CpG island in Sipa1 promoter-proximal elements could enhance SIPA1 expression in breast cancer cells, which could facilitate EMTof cancer cells, possibly increasing a risk of cancer cell metastasis in individuals treated with 5-Aza-CdR.