δEF1 associates with DNMT1 and maintains DNA methylation of the E-cadherin promoter in breast cancer cells.
δEF1 associates with DNMT1 and maintains DNA methylation of the E-cadherin promoter in breast cancer cells.
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ΔEF1与DNMT1相关，并维持乳腺癌细胞中电子钙粘蛋白启动子的DNA甲基化。
DOI：
10.1002/cam4.347
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发表时间：
2015-01
期刊：
影响因子：
4
通讯作者：
Saitoh, Masao
中科院分区：
文献类型：
--
作者：
Fukagawa, Akihiko;Ishii, Hiroki;Miyazawa, Keiji;Saitoh, Masao
在CpG二核苷酸的胞嘧啶的C-5位置（5mC）处的异常DNA甲基化是癌症的众所周知的表观遗传特征。在上皮组织中经常表达的E-钙粘蛋白的水平在上皮肿瘤中经常由于转录抑制而降低，有时伴随着启动子区域的超甲基化。δ EF1家族蛋白（δ EF1/ZEB1和SIP1/ZEB2）是上皮-间充质转化（EMT）的关键调节因子，在转录水平上抑制E-钙粘蛋白的表达。我们最近发现，在乳腺癌细胞中，编码δ EF1蛋白的mRNA水平与E-cadherin水平同时受到调节。在这里，我们研究了在三种基底型乳腺癌细胞中E-钙粘蛋白表达下调的机制，其中E-钙粘蛋白启动子区是高甲基化（Hs578T）或中度甲基化（BT549和MDA-MB-231）。无论甲基化状态如何，用抑制DNA甲基转移酶的5-aza-2 ′-脱氧胞苷（5-aza）处理对E-钙粘蛋白表达没有影响。敲低δ EF1和SIP1导致缺乏高甲基化的细胞中E-cadherin表达的恢复，而与5-aza联合处理协同恢复E-cadherin表达，特别是当E-cadherin启动子高甲基化时。此外，δ EF1还通过Smad结合结构域与DNA甲基转移酶1（DNMT1）相互作用。δ EF1家族蛋白的持续敲除减少了E-钙粘蛋白启动子区域中5mC位点的数量，表明这些蛋白通过与乳腺癌细胞中的DNMT 1相互作用来维持5mC。因此，δ EF1家族蛋白似乎在癌症进展期间直接在转录水平和间接在表观遗传水平抑制E-钙粘蛋白的表达。
Abnormal DNA methylation at the C-5 position of cytosine (5mC) of CpG dinucleotides is a well-known epigenetic feature of cancer. Levels of E-cadherin, which is regularly expressed in epithelial tissues, are frequently reduced in epithelial tumors due to transcriptional repression, sometimes accompanied by hypermethylation of the promoter region. δEF1 family proteins (δEF1/ZEB1 and SIP1/ZEB2), key regulators of the epithelial-mesenchymal transition (EMT), suppress E-cadherin expression at the transcriptional level. We recently showed that levels of mRNAs encoding δEF1 proteins are regulated reciprocally with E-cadherin level in breast cancer cells. Here, we examined the mechanism underlying downregulation of E-cadherin expression in three basal-type breast cancer cells in which the E-cadherin promoter region is hypermethylated (Hs578T) or moderately methylated (BT549 and MDA-MB-231). Regardless of methylation status, treatment with 5-aza-2′-deoxycytidine (5-aza), which inhibits DNA methyltransferases, had no effect on E-cadherin expression. Knockdown of δEF1 and SIP1 resulted in recovery of E-cadherin expression in cells lacking hypermethylation, whereas combined treatment with 5-aza synergistically restored E-cadherin expression, especially when the E-cadherin promoter was hypermethylated. Moreover, δEF1 interacted with DNA methyltransferase 1 (DNMT1) through the Smad-binding domain. Sustained knockdown of δEF1 family proteins reduced the number of 5mC sites in the E-cadherin promoter region, suggesting that these proteins maintain 5mC through interaction with DNMT1 in breast cancer cells. Thus, δEF1 family proteins appear to repress expression of E-cadherin during cancer progression, both directly at the transcriptional level and indirectly at the epigenetic level.
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影响因子：
--
作者：
Jin, Bilian;Robertson, Keith D.
通讯作者：
Robertson, Keith D.
影响因子：
8
作者：
Horiguchi, K.;Sakamoto, K.;Koinuma, D.;Semba, K.;Inoue, A.;Inoue, S.;Fujii, H.;Yamaguchi, A.;Miyazawa, K.;Miyazono, K.;Saitoh, M.
通讯作者：
Saitoh, M.
影响因子：
14.9
作者：
Espada J;Peinado H;Lopez-Serra L;Setién F;Lopez-Serra P;Portela A;Renart J;Carrasco E;Calvo M;Juarranz A;Cano A;Esteller M
通讯作者：
Esteller M
影响因子：
3
作者：
Singh, Varinder;Sharma, Prince;Capalash, Neena
通讯作者：
Capalash, Neena
影响因子：
2.1
作者：
Tatematsu, K;Yamazaki, T;Ishikawa, F
通讯作者：
Ishikawa, F