Inhibition of Epithelial to Mesenchymal Transition by E-cadherin Up-regulation via Repression of Slug Transcription and Inhibition of E-cadherin Degradation DUAL ROLE OF SCAFFOLD/MATRIX ATTACHMENT REGION-BINDING PROTEIN 1 (SMAR1) IN BREAST CANCER CELLS
Inhibition of Epithelial to Mesenchymal Transition by E-cadherin Up-regulation via Repression of Slug Transcription and Inhibition of E-cadherin Degradation DUAL ROLE OF SCAFFOLD/MATRIX ATTACHMENT REGION-BINDING PROTEIN 1 (SMAR1) IN BREAST CANCER CELLS
复制标题
DOI：
10.1074/jbc.m113.527267
复制
发表时间：
2014-09-12
影响因子：
4.8
通讯作者：
Das, Tanya
中科院分区：
文献类型：
--
作者：
Adhikary, Arghya;Chakraborty, Samik;Das, Tanya
癌细胞演变为转移实体是癌症患者死亡的主要原因。人们已经认识到，被称为上皮间质转化（EMT）的潜在胚胎程序的异常激活可以赋予癌细胞与转移能力相关的迁移和侵袭能力，而E-钙粘蛋白开关是其公认的标志。因此，了解调节 E-钙粘蛋白表达的分子机制对于了解肿瘤侵袭和转移至关重要。在这里，我们报告 SMAR1 过表达通过双向上调 E-cadherin 抑制 EMT 并减缓乳腺癌细胞的迁移潜力。虽然通过将 SMAR1/HDAC1 复合物直接招募到 Slug 启动子中存在的基质附着区域位点来对 Slug 进行 SMAR1 依赖性转录抑制，从而恢复 E-钙粘蛋白的表达，但 SMAR1 还阻碍 E-钙粘蛋白-MDM2 相互作用，从而减少 E-钙粘蛋白的泛素化和降解。一致地，siRNA敲低这些乳腺癌细胞中的SMAR1表达，导致Slug介导的E-钙粘蛋白转录抑制的协调作用，以及通过MDM2降解E-钙粘蛋白，上调乳腺癌细胞迁移。这些结果表明 SMAR1 在抑制乳腺癌细胞迁移中发挥着至关重要的作用，并表明这种支架基质相关区域结合蛋白作为肿瘤抑制因子的候选资格。
The evolution of the cancer cell into a metastatic entity is the major cause of death in patients with cancer. It has been acknowledged that aberrant activation of a latent embryonic program, known as the epithelial-mesenchymal transition (EMT), can endow cancer cells with the migratory and invasive capabilities associated with metastatic competence for which E-cadherin switch is a well-established hallmark. Discerning the molecular mechanisms that regulate E-cadherin expression is therefore critical for understanding tumor invasiveness and metastasis. Here we report that SMAR1 overexpression inhibits EMT and decelerates the migratory potential of breast cancer cells by up-regulating E-cadherin in a bidirectional manner. While SMAR1-dependent transcriptional repression of Slug by direct recruitment of SMAR1/HDAC1 complex to the matrix attachment region site present in the Slug promoter restores E-cadherin expression, SMAR1 also hinders E-cadherin-MDM2 interaction thereby reducing ubiquitination and degradation of E-cadherin protein. Consistently, siRNA knockdown of SMAR1 expression in these breast cancer cells results in a coordinative action of Slug-mediated repression of E-cadherin transcription, as well as degradation of E-cadherin protein through MDM2, up-regulating breast cancer cell migration. These results indicate a crucial role for SMAR1 in restraining breast cancer cell migration and suggest the candidature of this scaffold matrix-associated region-binding protein as a tumor suppressor.