An antisense circular RNA circSCRIB enhances cancer progression by suppressing parental gene splicing and translation

Circular RNAs (circRNAs) represent a large group of non-cod-ing RNAs that are widely detected in mammalian cells. Although most circRNAs are generated in a sense orientation, there is a group of circRNAs that are synthesized in an anti-sense orientation. High-throughput analysis of breast cancer specimens revealed a significant enrichment of 209 antisense circRNAs. The tumor suppressor SCRIB was shown to poten-tially produce thirteen circRNAs, three of which are in an anti-sense orientation. Among these three circRNAs, circSCRIB (hsa_circ_0001831) was the most enriched in the breast cancer panel. This antisense SCRIB circRNA was shown to span one intron and two exons. We hypothesized that this circRNA could decrease pre-mRNA splicing and mRNA translation. To test this, we generated a hsa_circ_0001831 expression construct. We found that there was decreased SCRIB mRNA production but increased cancer cell proliferation, migration, and invasion. In comparison, an exonic sequence construct did not affect mRNA splicing but decreased protein transla-tion, leading to increased E-cadherin expression and decreased expression of N-cadherin and vimentin. Thus, there was increased cell migration, invasion, proliferation, colony forma-tion, and tumorigenesis. Our study suggests a novel modula-tory role of antisense circRNAs on their parental transcripts. This may represent a promising approach for developing circRNA-directed therapy.