EIF4A3-Induced circARHGAP29 Promotes Aerobic Glycolysis in Docetaxel-Resistant Prostate Cancer through IGF2BP2/c-Myc/LDHA Signaling.

Docetaxel-based chemotherapy is a standard-of-care treatment for metastatic prostate cancer, and chemoresistance remains a major challenge in clinical practice. Recent studies have demonstrated that circular RNAs (circRNA) play critical roles in the development and progression of prostate cancer. However, the biological roles and potential functions of circRNAs in mediating docetaxel-resistant prostate cancer have yet to be well elucidated. In this study, we analyzed the expression profiles of circRNAs in docetaxel-resistant and -sensitive prostate cancer cells through RNA sequencing and found that expression of circARHGAP29 was significantly upregulated in docetaxel-resistant cell lines and clinical samples. Ectopic expression of circARHGAP29 triggered docetaxel resistance and aerobic glycolysis in prostate cancer cells, which was reduced by silencing circARHGAP29. Moreover, eukaryotic initiation factor 4A3, which bound the back-spliced junction site and the downstream flanking sequence of circARHGAP29, induced cyclization and cytoplasmic export of circARHGAP29. circARHGAP29 increased the stability of lactate dehydrogenase A (LDHA) mRNA by strengthening its interaction with insulin-like growth factor 2 mRNA-binding protein 2, leading to enhanced glycolytic metabolism. In addition, circARHGAP29 interacted with and stabilized c-Myc mRNA and protein, which further increased LDHA expression by facilitating its transcription. These findings reveal the crucial function of circARHGAP29 in prostate cancer glycolysis by increasing and stabilizing LDHA mRNA, providing a promising therapeutic target in docetaxel-resistant prostate cancer. SIGNIFICANCE: Upregulation of a novel circRNA, circARHGAP29, promotes docetaxel resistance and glycolytic metabolism, suggesting it could be a prognostic biomarker and therapeutic target in chemoresistant prostate cancer. ©2021 American Association for Cancer Research.