KDM8/c-Myc axis-mediated glucose metabolism reprogramming promotes the progression of ovarian cancer

Abstract Both KDM8 and c-Myc have been implicated in regulating tumor glucose metabolism. However, whether there is an interaction between KDM8 and c-Myc, and whether KDM8 function is dependent on c-Myc in ovarian cancer (OC) remains unclear. Paired cancerous and paracancerous tissues from five OC patients were analyzed for KDM8 and c-Myc expression using reverse transcription quantitative polymerase chain reaction and Western blot. Co-Immunoprecipitation assays were conducted to verify their potential interaction. Stable OVCAR3 and SKOV3 cell lines overexpressing KDM8 or c-Myc were established. Functional assays (CCK-8, Transwell, colony formation, wound healing, and flow cytometry) were performed to assess proliferation, migration, invasion, colony formation, and apoptosis. Metabolic changes were evaluated by measuring glucose uptake and lactate accumulation using colorimetric and ELISA kits, respectively. Finally, a nude mouse subcutaneous xenograft model was constructed to observe the growth and metabolic levels of OC in vivo. Both mRNA and protein levels of KDM8 and c-Myc were significantly upregulated in ovarian cancer (OC) tissues compared to paracancerous tissues. Furthermore, a direct interaction between KDM8 and c-Myc was identified. Functionally, KDM8 and c-Myc synergistically promoted the malignant behavior of OC cells, including enhanced proliferation, migration, invasion, and colony formation capacities. Additionally, they promoted metabolic reprogramming, as evidenced by increased glucose uptake and lactate accumulation, while concurrently inhibiting apoptosis. However, siRNA-mediated knockdown of c-Myc significantly attenuated these oncogenic effects, reversing the enhanced proliferative, migratory, and metabolic capacities of OC cells. In vivo experiments further verified that the KDM8 /c-Myc axis affects OC growth and metabolic levels. Collectively, our findings indicate that KDM8 and c-Myc cooperate to promote OC progression, which may be mediated through the regulation of glucose metabolism. Notably, KDM8 function is partially dependent on c-Myc in this context. These results provide preliminary evidence supporting KDM8 as a potential candidate target for OC diagnosis and treatment, with further validation required in larger cohorts.