m(6)A-Mediated Biogenesis of circDDIT4 Inhibits Prostate Cancer Progression by Sequestrating ELAVL1/HuR

The pathologic significance of the circular RNA DDIT4 (circDDIT4), which is formed by backsplicing at the 3′-untranslated region (UTR) with a 5′ splice acceptor site in exon 2 of linear DDIT4 mRNA, has yet to be determined. Our study found that circDDIT4 is downregulated in prostate cancer and functions as a tumor suppressor during prostate cancer progression. By competitively binding to ELAV-like RNA binding protein 1 (ELAVL1/HuR) through its 3′-UTR, circDDIT4 acts as a protein sponge to decrease the expression of prostate cancer–overexpressed anoctamin 7 (ANO7). This promotes prostate cancer cell apoptosis while inhibiting cell proliferation and metastasis. Furthermore, we discovered that N6-methyladenosine (m6A) modification facilitates the biogenesis of circDDIT4. The methyltransferase complex consisting of WTAP/METTL3/METTL14 increases the level of circDDIT4, while the RNA demethylase FTO decreases it. IMPLICATIONS: These findings suggest that abnormal cotranscriptional modification of m(6)A promotes prostate cancer initiation and progression via a circular RNA-protein-cell signaling network.