Direct circMAN1A2(2,3,4,5)-CENPB mRNA interaction regulates cell proliferation and cancer progression

A large number of covalently closed circular RNAs (circRNAs), produced from back-splicing of eukaryotic exons, have been identified among different cell lines/tissues. Interestingly, multiple circRNAs could be produced from a single gene locus through alternative circularization (AC), expanding the complexity and diversity of circRNAs. However, functions of most AC circRNAs remains poorly understood. Here, we profiled the landscape of AC across multiple cell lines and colorectal cancer (CRC) tissues, identifying predominantly expressed circRNAs (pe-circRNA) in each AC gene loci. While the expression of top pe-circRNAs exhibits a cell-type-specific manner, circMAN1A2(2,3,4,5), a pe-circRNA that is universally expressed in examined cells and CRC samples, was shown to play an important role in cell proliferation and CRC progression. Mechanistically, circMAN1A2(2,3,4,5) directly interacted with the 3' untranslated region of Centromere Protein B (CENPB) mRNA via its characteristic back-splicing junction site, which enhanced IGF2BP2-mediated CENPB mRNA stability. Inhibition of circMAN1A2(2,3,4,5) expression with specific shRNAs and locked nucleic acids (LNAs) resulted in repressed cell proliferation and tumor progression in the subcutaneous mouse CRC model. These results together uncover the prevalence of AC and the regulatory role of a specific AC circRNA, circMAN1A2(2,3,4,5), in cell proliferation and tumor progression.