O‐GlcNAcylation promotes topoisomerase IIα catalytic activity in breast cancer chemoresistance

Abstract DNA topoisomerase IIα (TOP2A) plays a vital role in replication and cell division by catalytically altering DNA topology. It is a prominent target for anticancer drugs, but clinical efficacy is often compromised due to chemoresistance. In this study, we investigate the role of TOP2A O ‐GlcNAcylation in breast cancer cells and patient tumor tissues. Our results demonstrate that elevated TOP2A, especially its O ‐GlcNAcylation, promotes breast cancer malignant progression and resistance to adriamycin (Adm). O ‐GlcNAcylation at Ser1469 enhances TOP2A chromatin DNA binding and catalytic activity, leading to resistance to Adm in breast cancer cells and xenograft models. Mechanistically, O ‐GlcNAcylation‐modulated interactions between TOP2A and cell cycle regulators influence downstream gene expression and contribute to breast cancer drug resistance. These results reveal a previously unrecognized mechanistic role for TOP2A O ‐GlcNAcylation in breast cancer chemotherapy resistance and provide support for targeting TOP2A O ‐GlcNAcylation in cancer therapy.