RNA结合蛋白（RBPs）对癌症进展有贡献，但其基本机制尚不清楚。在这里，我们发现DDX21，一种代表性的RBP，在结直肠癌（CRC）中高表达，导致CRC细胞在体外迁移和侵袭，以及CRC向肝脏和肺转移。DDX21对CRC转移的这种影响与上皮-间充质转化（EMT）途径的激活有关。此外，我们揭示了DDX21蛋白在体外和CRC细胞中的相分离作用，其可控制CRC的转移。相分离DDX21高度结合MCM5基因座，当相分离受其内在无序区（IDR）突变的干扰时，这种结合显著降低。DDX21丧失对CRC的转移能力被MCM5的异位表达恢复，表明MCM5是DDX21调节CRC转移的关键下游目标。此外，DDX21和MCM5的共高表达与III和IV期CRC患者的不良生存结局显著相关，表明这种机制在CRC晚期和转移期的重要性。总之，我们的研究结果揭示了DDX21通过相分离调节CRC转移的新模型。© 2023. The Author(s)。

RNA binding proteins (RBPs) contributes to cancer progression, but the underlying mechanism reminds unclear. Here, we find that DDX21, a representative RBP, is highly expressed in colorectal cancer (CRC), which leads to CRC cell migration and invasion in vitro, and CRC to liver metastasis and lung metastasis in vivo. This effect of DDX21 on CRC metastasis is correlated to the activation of Epithelial-mesenchymal transition (EMT) pathway. Moreover, we reveal that DDX21 protein is phase separated in vitro and in CRC cells, which controls CRC metastasis. Phase-separated DDX21 highly binds on MCM5 gene locus, which is markedly reduced when phase separation is disrupted by mutations on its intrinsically disordered region (IDR). The impaired metastatic ability of CRC upon DDX21 loss is restored by ectopic expression of MCM5, indicating MCM5 is a key downstream target of DDX21 for CRC metastasis. Furthermore, co-higher expressions of DDX21 and MCM5 is significantly correlated with poor survival outcomes of stage III and IV CRC patients, indicating the importance of this mechanism in CRC late and metastatic stage. Altogether, our results elucidate a new model of DDX21 in regulating CRC metastasis via phase separation.© 2023. The Author(s).