Abstract

Colorectal cancer (CRC) progression is critically associated with metastasis, yet the molecular drivers remain incompletely characterized. Here, we identify circFAT1, a circular RNA derived from exon 2 of the tumor suppressor gene FAT1, as a metastasis-promoting factor in CRC. Through polysome profiling and RNA sequencing, we demonstrate that circFAT1 is upregulated in CRC tissues and exhibits translational activity. Functional assays reveal that circFAT1 encodes a novel 1057-amino acid protein that enhances CRC cell migration, invasion, and metastatic dissemination in vivo, independent of proliferation. Mechanistically, the circFAT1-encoded protein interacts with DDX17 to facilitate β-catenin nuclear translocation, forming a ternary complex that binds promoter regions of RHOA and FRAT1 to activate their transcription. This axis drives epithelial-mesenchymal transition (EMT), as evidenced by downregulation of E-cadherin and upregulation of N-cadherin, vimentin, ZEB1 and Snail. Strikingly, linear FAT1 inversely suppresses CRC cell motility, highlighting the functional dichotomy between circular and linear isoforms. Our findings establish circFAT1 as a pro-metastatic driver in CRC and provide a mechanistic framework for targeting the circFAT1/DDX17/β-catenin signaling axis in therapeutic strategies.