The TWIST/Mi2/NuRD protein complex and its essential role in cancer metastasis
The TWIST/Mi2/NuRD protein complex and its essential role in cancer metastasis
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DOI：
10.1038/cr.2010.118
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发表时间：
2011-02-01
期刊：
影响因子：
44.1
通讯作者：
Xu, Jianming
中科院分区：
文献类型：
--
作者：
Fu, Junjiang;Qin, Li;Xu, Jianming
上皮-间质转化（EMT）将上皮肿瘤细胞转化为侵袭性和转移性癌细胞，导致癌症患者死亡。虽然TWIST是乳腺癌和其他癌症的EMT和转移的主要调节因子，但负责TWIST介导的基因转录的机制仍然未知。在这项研究中，TWIST蛋白复合物的纯化和表征显示，TWIST与Mi2/核小体重塑和脱乙酰酶（Mi2/NuRD）复合物的几种组分MTA 2，RbAp 46，Mi2和HDAC 2相互作用，并将它们招募到E-钙粘蛋白启动子的近端区域进行转录抑制。从依赖于TWIST转移的癌细胞系中消耗这些TWIST复合物组分有效地抑制了培养物中的细胞迁移和侵袭以及小鼠中的肺转移。这些发现不仅提供了TWIST和Mi2/NuRD复合物之间的新机制和功能联系，而且还为Mi2/NuRD复合物的组分在癌症转移中建立了新的重要作用。
The epithelial-mesenchymal transition (EMT) converts epithelial tumor cells into invasive and metastatic cancer cells, leading to mortality in cancer patients. Although TWIST is a master regulator of EMT and metastasis for breast and other cancers, the mechanisms responsible for TWIST-mediated gene transcription remain unknown. In this study, purification and characterization of the TWIST protein complex revealed that TWIST interacts with several components of the Mi2/nucleosome remodeling and deacetylase (Mi2/NuRD) complex, MTA2, RbAp46, Mi2 and HDAC2, and recruits them to the proximal regions of the E-cadherin promoter for transcriptional repression. Depletion of these TWIST complex components from cancer cell lines that depend on TWIST for metastasis efficiently suppresses cell migration and invasion in culture and lung metastasis in mice. These findings not only provide novel mechanistic and functional links between TWIST and the Mi2/NuRD complex but also establish new essential roles for the components of Mi2/NuRD complex in cancer metastasis.