Downregulation of O‐ GlcNAcylation enhances etoposide‐induced p53‐mediated apoptosis in HepG2 human liver cancer cells

Etoposide, an anticancer drug that inhibits topoisomerase II, is commonly used in combination chemotherapy. However, the impact of O‐GlcNAcylation regulation on etoposide's anticancer effects has rarely been investigated. This study evaluated the effect of etoposide on cellular O‐GlcNAcylation and whether modulating this process enhances etoposide‐induced apoptosis. O‐GlcNAc expression was measured after 24 h of etoposide treatment, and the effect of O‐GlcNAc transferase (OGT) inhibition by OSMI‐1 on etoposide's anticancer activity in HepG2 human liver cancer cells was quantitatively analyzed. Additionally, molecular analyses were used to confirm that the observed effects were mediated by p53‐induced apoptosis. Etoposide reduced O‐GlcNAcylation in a dose‐dependent manner without directly interacting with OGT. Cotreatment with 20 μ m of OSMI‐1 lowered the IC 50 value for cell viability by approximately 1.64‐fold to 60.68 μ m and increased the EC 50 value for cytotoxicity by around 4.07‐fold to 43.41 μ m . Furthermore, this synergistic effect was linked to the activation of the p53/caspase‐3/PARP1 pathway. These findings suggest that downregulating O‐GlcNAcylation may enhance the efficacy of etoposide‐based chemotherapy and help overcome tumor resistance.