CDKN3 Overcomes Bladder Cancer Cisplatin Resistance via LDHA-Dependent Glycolysis Reprogramming

BACKGROUND: Aerobic glycolysis plays an important role in bladder cancer (BLCA) progression and chemoresistance. Cyclin-dependent kinase inhibitor-3 (CDKN3), a dual-specificity protein tyrosine phosphatase, has aberrant upregulation in multiple cancer types and is associated with tumorigenesis. However, the role of CDKN3 in BLCA progression and glycolysis has not been elucidated. PURPOSE: In this study, we investigated the effect and underlying mechanisms of CDKN3 on bladder cancer chemoresistance. RESULTS: This study confirmed that CDKN3 was overexpressed in BLCA tissues and promoted proliferation and migration. Additionally, our results showed a CDKN3-dependent mechanism on chemoresistance; chemoresistance cells were transformed into chemosensitivity cells by CDKN3 knockdown. Additionally, we showed that CDKN3 knockdown decreased glycolysis by inhibiting LDHA expression in BLCA chemoresistance cells. The results also proved that LDHA was an important mediator of CDKN3-regulated BLCA resistance. LDHA overexpression reversed glycolysis inhibition and chemosensitivity induced by CDKN3 downregulation. CONCLUSION: These data collectively identified a vital role of CDKN3 in glycolysis and chemoresistance by regulating LDHA expression in BLCA cells, providing a possible therapeutic strategy for treating BLCA.