HNRNPL Circularizes ARHGAP35 to Produce an Oncogenic Protein

Circular RNAs (circRNAs) are an intriguing class of widely prevalent endogenous RNAs, the vast majority of which have not been characterized functionally. Here, we identified a novel oncogenic circRNA originating from the back‐splicing of Exon2 and Exon3 of a tumor suppressor gene, ARHGAP35 (also known as P190‐A), termed as circARHGAP35. have observe that circARHGAP35 and linear ARHGAP35 have antithetical expression and functions. Interestingly, circARHGAP35 contains a 3867 nt long ORF with an m6A‐modified start codon and encodes a truncated protein comprising four FF domains and lacking the Rho GAP domain. Mechanistically, circARHGAP35 protein promotes cancer cell progression by interacting with TFII‐I protein in the nucleus. The RNA binding protein, HNRNPL, facilitates the formation of circARHGAP35. Clinically, circARHGAP35 is associated with poor survival in cancer patients. Our findings characterize an oncogenic circRNA and demonstrate a novel mechanism of oncogene activation in cancer by circRNA through the production of a truncated protein. Herein, the role of circular RNAs (circRNAs) in cancer is investigated. circARHGAP35 and linear ARHGAP35 are observed to have antithetical expression and functions in cancer. circARHGAP35 translates into an oncogenic large protein that binds to TFII‐I and promotes cancer progression, while its linear counterpart encodes a tumor suppressor. N6‐methyladenosine (m6A) modification of circARHGAP35 promotes its protein translation, and HNRNPL boosts the biogenesis of circARHGAP35.