CircDOPEY2 promotes prostate cancer metastasis via inhibiting heterogeneous nuclear ribonucleoprotein M ubiquitination to stabilize intercellular adhesion molecule 2 mRNA.

Prostate cancer (PCa) ranks among the most prevalent malignancies affecting the male population worldwide, and metastatic PCa (mPCa) carries a poor prognosis. Circular RNAs (circRNAs), a distinct class of RNAs, have been implicated in the progression of various tumors. However, their specific biological functions and underlying mechanisms in PCa, particularly in mPCa, remain largely undefined. In this study, we identified a novel circRNA derived from the back-splicing of exons 20-21 of the Dopey Family Member 2 (DOPEY2) gene. This circRNA, which we named circDOPEY2, was highly expressed in PCa. The circDOPEY2 expression was significantly correlated with multiple clinicopathological indicators associated with PCa severity and prognosis, including Gleason score, clinical M stage, and D'Amico risk classification. Functional assays demonstrated that circDOPEY2 significantly promoted PCa cell metastasis both in vitro and in vivo. Mechanistically, circDOPEY2 directly bound to heterogeneous nuclear ribonucleoprotein M and inhibited its degradation via the ubiquitin-proteasome pathway. The resulting stabilization of heterogeneous nuclear ribonucleoprotein M upregulated the intercellular adhesion molecule 2 expression by enhancing the stability of its mRNA, ultimately promoting PCa metastasis. Moreover, serine/arginine-rich splicing factor 1 mediates circDOPEY2 biogenesis through specific interactions with AluSx1 and AluSx elements. In summary, our findings identify circDOPEY2 as a key promoter of PCa metastasis, highlighting its potential as both a clinical biomarker and therapeutic target for mPCa. SIGNIFICANCE STATEMENT: This study identifies circDOPEY2 as a driver of prostate cancer (PCa) metastasis. Mechanistically, circDOPEY2 inhibits heterogeneous nuclear ribonucleoprotein M ubiquitin-proteasome degradation, stabilizing it to upregulate intercellular adhesion molecule 2 and promote PCa metastasis. This study also provides the first evidence that serine/arginine-rich splicing factor 1 interacts with Alu sequences to regulate circDOPEY2 biogenesis. These findings highlight circDOPEY2 as a novel clinical biomarker and therapeutic target for metastatic PCa.