Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Cell Res. 2011 Feb;21(2):275-89. doi: 10.1038/cr.2010.118. Epub 2010 Aug 17.
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.
上皮-间充质转化 (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。尽管 TWIST 是乳腺癌和其他癌症 EMT 和转移的主要调节因子，但 TWIST 介导的基因转录的机制仍不清楚。在这项研究中，TWIST 蛋白复合物的纯化和表征揭示了 TWIST 与 Mi2/核小体重塑和去乙酰化酶 (Mi2/NuRD) 复合物、MTA2、RbAp46、Mi2 和 HDAC2 的几个成分相互作用，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 TWIST 进行转移的癌细胞系中耗尽这些 TWIST 复合物成分，可有效抑制细胞在培养中的迁移和侵袭以及在小鼠中的肺转移。这些发现不仅为 TWIST 和 Mi2/NuRD 复合物之间提供了新的机制和功能联系，而且还确立了 Mi2/NuRD 复合物成分在癌症转移中的新的重要作用。
