| Summary: | Increasing evidence has implicated that circular RNAs (circRNAs) exert important roles in colorectal cancer (CRC) occurrence and progression. However, the role of a novel circRNA, <i>circUHRF2</i>, remains unknown in CRC. Our work aimed at identifying the functional roles of <i>circUHRF2</i> in CRC and illustrating the potential mechanisms. As assessed by quantitative real-time PCR (qRT-PCR), <i>circUHRF2</i> and methyltransferase-like 3 (METTL3) were highly expressed in CRC specimens and cells. Sanger sequencing and RNase R assays were performed to verify the ring structure of <i>circUHRF2</i>. Notably, aberrantly increased expression of <i>circUHRF2</i> was positively correlated with poor prognosis of CRC patients. Functional experiments indicated that CRC stemness, migration, and epithelial-mesenchymal transition (EMT) were suppressed by the knockdown of <i>circUHRF2</i> or METTL3. Mechanistically, METTL3 enhanced <i>circUHRF2</i> expression through N6-methyladenine (m<sup>6</sup>A) modification. Rescue experiments showed that overexpression of <i>circUHRF2</i> reversed the repressive effect of METTL3 silencing on CRC progression. Moreover, <i>circUHRF2</i> inhibited the loss of DEAD-box helicase 27 (DDX27) protein via promoting the interaction between insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) and <i>DDX27</i> mRNA. DDX27 knockdown repressed CRC malignant properties, which was counteracted by <i>circUHRF2</i> overexpression. The in vivo assays in nude mice demonstrated that <i>circUHRF2</i> or METTL3 silencing exerted a suppressive effect on CRC growth and liver metastasis via repressing DDX27 protein expression. Taken together, METTL3-mediated m<sup>6</sup>A modification upregulated <i>circUHRF2</i> and subsequently inhibited loss of DDX27 protein via recruitment of IGF2BP1, which conferred CRC stemness and metastasis. These findings shed light on CRC pathogenesis and suggest <i>circUHRF2</i> as a novel target for CRC treatment.
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