Montreal Clinical Research Institute (IRCM), Montréal, QC H2W 1R7, Canada.
Montreal Clinical Research Institute (IRCM), Montréal, QC H2W 1R7, Canada; Molecular Biology Programs, Université de Montréal, Montréal, QC H3T 1J4, Canada.
Cell Rep. 2018 Jan 23;22(4):1016-1030. doi: 10.1016/j.celrep.2017.12.096. Epub 2018 Jan 28.
Cancer cells exploit the epithelial-to-mesenchymal transition (EMT) program to become metastatic. Cytoskeletal regulators are required in mesenchymal cells where they promote EMT and EMT-induced migration. In a search for regulators of metastasis, we conducted shRNA screens targeting the microtubule plus-end tracking proteins (+TIPs). We show that the +TIP ACF7 is essential both for the maintenance of the EMT program and to promote migration. We find that the E3 ubiquitin ligase HectD1 promotes ACF7-proteasome-mediated degradation. Depletion of HectD1 stabilized ACF7, and this enhanced EMT and migration. Decreased HectD1 expression increased metastases in mouse models and conferred increased resistance to the cytotoxic drug cisplatin. A retrospective analysis of biopsies from breast cancer patients also reveals a correlation between higher ACF7 or lower HectD1 expression with poor clinical outcomes. Together, these results suggest that the control of ACF7 levels by HectD1 modulates EMT and the efficiency of metastasis.
癌细胞利用上皮间质转化（EMT）程序成为转移性的。细胞骨架调节剂在间质细胞中是必需的，它们促进 EMT 和 EMT 诱导的迁移。在寻找转移的调节剂时，我们针对微管正端追踪蛋白（+TIPs）进行了 shRNA 筛选。我们表明，+TIP ACF7 对于 EMT 程序的维持和促进迁移都是必不可少的。我们发现 E3 泛素连接酶 HectD1 促进 ACF7-蛋白酶体介导的降解。HectD1 的耗竭稳定了 ACF7，从而增强了 EMT 和迁移。减少 HectD1 的表达增加了小鼠模型中的转移，并赋予了对细胞毒性药物顺铂更高的耐药性。对乳腺癌患者活检的回顾性分析也表明，ACF7 表达较高或 HectD1 表达较低与临床预后不良相关。总之，这些结果表明，HectD1 对 ACF7 水平的控制调节 EMT 和转移的效率。
