A novel FOXM1 isoform, FOXM1D, promotes epithelial-mesenchymal transition and metastasis through ROCKs activation in colorectal cancer.
A novel FOXM1 isoform, FOXM1D, promotes epithelial-mesenchymal transition and metastasis through ROCKs activation in colorectal cancer.
复制标题
一种新型 FOXM1 亚型 FOXM1D 通过 ROCK 激活结直肠癌促进上皮间质转化和转移。
作者：
Zhang X;Zhang L;Du Y;Zheng H;Zhang P;Sun Y;Wang Y;Chen J;Ding P;Wang N;Yang C;Huang T;Yao X;Qiao Q;Gu H;Cai G;Cai S;Zhou X;Hu W
上皮-间质转化（EMT）是结直肠癌（CRC）转移的关键事件。Rho/ROCKs信号传导在协调肌动蛋白细胞骨架中具有关键作用，导致EMT和癌症侵袭。然而，ROCKs激活的潜在机制尚未完全了解。在这里，我们确定FOXM 1D，叉头盒M1（FOXM 1）的一种新型亚型，通过直接与ROCK 2的卷曲螺旋区域相互作用，在ROCKs激活中发挥关键作用。FOXM 1D过表达显著聚合肌动蛋白组装并损害E-钙粘蛋白表达，导致异种移植小鼠模型中的EMT和转移，而FOXM 1D敲低具有相反的效果。此外，高FOXM 1D水平与临床CRC转移密切相关。ROCKs抑制剂Y-27632和法舒地尔可阻断FOXM 1D诱导的ROCKs激活。这些观察结果表明FOXM 1D-ROCK 2相互作用对于Rho/ROCKs信号传导至关重要，并为CRC转移的肌动蛋白细胞骨架调节和治疗潜力提供了新的见解。
Epithelial–mesenchymal transition (EMT) is a critical event in metastasis of colorectal cancer (CRC). Rho/ROCKs signaling has a pivotal role in orchestrating actin cytoskeleton, leading to EMT and cancer invasion. However, the underlying mechanisms for ROCKs activation are not fully understood. Here, we identified FOXM1D, a novel isoform of Forkhead box M1 (FOXM1) that has a pivotal role in ROCKs activation by directly interacting with coiled-coil region of ROCK2. FOXM1D overexpression significantly polymerizes actin assembly and impairs E-cadherin expression, resulting in EMT and metastasis in xenograft mouse model and knockdown of FOXM1D has the opposite effect. Moreover, a high FOXM1D level correlates closely with clinical CRC metastasis. FOXM1D-induced ROCKs activation could be abrogated by the ROCKs inhibitors Y-27632 and fasudil. These observations indicate that the FOXM1D–ROCK2 interaction is crucial for Rho/ROCKs signaling and provide novel insight into actin cytoskeleton regulation and therapeutic potential for CRC metastasis.