A novel FOXM1 isoform, FOXM1D, promotes epithelial-mesenchymal transition and metastasis through ROCKs activation in colorectal cancer

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.^*

来源：Oncogene, 2017, 36(6): 807-819.

DOI：10.1038/onc.2016.249

• FORKHEAD BOX M1
• RHO-ASSOCIATED KINASE
• COILED-COILS
• TARGET
• TUMORIGENESIS
• TRANSCRIPTION
• PROGRESSION
• INHIBITION
• EXPRESSION
• INVASION

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.

• 出版日期2017-2-9
• 单位复旦大学; 中国人民解放军第二军医大学; 天津市中医药研究院附属医院