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.
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