Up-regulation of MBD1 promotes pancreatic cancer cell epithelial-mesenchymal transition and invasion by epigenetic down-regulation of E-cadherin.
Up-regulation of MBD1 promotes pancreatic cancer cell epithelial-mesenchymal transition and invasion by epigenetic down-regulation of E-cadherin.
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MBD1的上调通过E-钙粘蛋白的表观遗传下调促进胰腺癌细胞上皮-间质转化和侵袭。
DOI：
10.2174/1566524011313030008
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发表时间：
2013-02
影响因子：
2.5
通讯作者：
Yu X
中科院分区：
文献类型：
--
作者：
Liu C;Long J;Ni Q;Yu X
甲基化CpG结合域蛋白1（MBD 1）参与转录调控、异染色质形成、基因组稳定性、细胞周期进展和发育。MBD 1可能参与肿瘤的发生和发展。然而，MBD 1是否以及如何参与肿瘤发生，特别是胰腺癌（PC），目前尚不清楚。RT-PCR结果显示MBD 1在胰腺癌组织中的表达明显高于癌旁正常组织。组织芯片（TMA）免疫组化研究表明，高MBD 1表达与PC患者的淋巴结转移和生存率低。体外功能获得和丧失研究证实MBD 1是促进PC细胞侵袭以及上皮-间质转化（EMT）的有效致癌基因。从机制上讲，MBD 1与Twist和NAD依赖性脱乙酰酶sirtuin-1（SIRT 1）相关，从而在CDH 1启动子上形成Twist-MBD 1-SIRT 1复合物，这导致E-钙粘蛋白转录活性降低和细胞EMT能力增加。值得注意的是，靶向MBD 1逆转了PC的EMT表型，并恢复了对化疗的敏感性。总之，我们的研究结果揭示了MBD 1在PC侵袭和转移中的新功能，提供了MBD 1促进EMT的分子机制。因此，MBD 1可能作为PC的潜在治疗靶点。
Methyl-CpG binding domain protein 1 (MBD1) has been implicated in transcriptional regulation, heterochromatin formation, genomic stability, cell-cycle progression and development. It is also predicted that MBD1 might be involved in tumor development and progression. However, whether and how MBD1 is involved in tumorigenesis, especially in pancreatic cancer (PC), is currently unknown. We found that MBD1 was significantly up-regulated in PC tissues compared with the surrounding normal tissues according to RT-PCR data. Tissue microarray (TMA) based immunohistochemical study from 58 surgically resected PC specimens indicated that higher MBD1 expression correlated with lymph node metastasis and poor survival in PC patients. Gain- and loss-of-function studies in vitro validated MBD1 as a potent oncogene promoting PC cell invasion as well as epithelial-mesenchymal transition (EMT). Mechanistically, MBD1 is associated with Twist and NAD-dependent deacetylase sirtuin-1 (SIRT1), thereby forming the Twist-MBD1-SIRT1 complex on the CDH1 promoter, which resulted in reduced E-cadherin transcription activity and increased cell EMT ability. Significantly, targeting MBD1 reversed the EMT phenotype of PC and restored sensitivity to chemotherapy. Taken together, the results of our study revealed a novel function of MBD1 in PC invasion and metastasis by providing a molecular mechanism underlying MBD1-promoted EMT. Thus MBD1 may serve as a potential therapeutic target for PC.
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DOI：
10.1016/j.biocel.2007.07.011
发表时间：
2007-01-01
影响因子：
4
作者：
Guarino, Marcello
通讯作者：
Guarino, Marcello
DOI：
10.1891/9780826121646.0002
发表时间：
2018-09
期刊：
Cancer Rehabilitation
影响因子：
--
作者：
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通讯作者：
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影响因子：
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作者：
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Baylin SB
SET8促进上皮间质转化并赋予TWIST双重转录活性
影响因子：
11.4
作者：
Yang, Fen;Sun, Luyang;Shang, Yongfeng
通讯作者：
Shang, Yongfeng
影响因子：
64.5
作者：
Yang, J;Mani, SA;Weinberg, RA
通讯作者：
Weinberg, RA