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

Abstract

AbstractDNA 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.