Liver metastasis remains the predominant contributor to mortality in individuals diagnosed with colorectal cancer (CRC). Growing research highlights the significant involvement of circular RNA (circRNA) in driving cancer advancement. Nonetheless, the specific role of circRNA in the development of liver metastasis in CRC remains unclear. Circ-YAP expression levels were assessed by quantitative real-time PCR and in situ hybridization. Functional roles of circ-YAP were investigated using wound-healing assays, transwell migration/invasion assays, and CCK-8 proliferation assays. To explore the underlying molecular pathways through which circ-YAP facilitates CRC liver metastasis, RNA immunoprecipitation, RNA pull-down, luciferase reporter, and chromatin immunoprecipitation assays were performed. Additionally, an in vivo CRC liver metastasis model was developed to determine the influence of circ-YAP in animal systems. Circ-YAP was markedly elevated in CRC specimens with liver metastasis, and this elevation was strongly associated with unfavorable clinical outcomes. In vitro experiments demonstrated that circ-YAP enhanced the migratory and invasive capabilities of CRC cells. In vivo studies using patient-derived xenograft (PDX) models further confirmed its ability to promote liver metastasis. At the mechanistic level, circ-YAP produces a previously unidentified truncated protein, YAP-220aa, consisting of 220 amino acids. This protein competitively binds LATS1, thereby inhibiting YAP phosphorylation, promoting its nuclear localization, and subsequently stimulating the expression of multiple genes involved in metastasis. Notably, the N6-methyladenosine (m6A) modification plays a crucial role in enabling efficient translation of circ-YAP, relying on the m6A reader protein YTHDF3 and the eIF4G2-containing translation initiation complex. Furthermore, the YAP/TEAD complex was found to transcriptionally upregulate circ-YAP expression, thereby creating a positive feed-forward regulatory circuit. These results identify a novel oncoprotein, circ-YAP, that has not been previously described, suggesting its value as a potential biomarker and therapeutic target for managing liver metastasis in CRC patients.
