# OGT‐Mediated O‐GlcNAcylation Stabilizes c‐Myc Activity and Promotes Chemoresistance in Triple‐Negative Breast Cancer

## TL;DR

This study shows that OGT-mediated O-GlcNAcylation stabilizes c-Myc and promotes chemoresistance in triple-negative breast cancer.

## Contribution

The study identifies Thr-58 as a novel O-GlcNAcylation site on c-Myc that regulates its stability and chemoresistance in TNBC.

## Key findings

- Inhibition of OGT reduces c-Myc stability and chemoresistance in TNBC cells.
- O-GlcNAcylation at Thr-58 promotes c-Myc activity and colony formation.
- Mutation of Thr-58 decreases c-Myc expression and increases apoptosis in resistant cells.

## Abstract

The transcription factor c‐Myc is often overexpressed in chemotherapy‐resistant triple‐negative breast cancer (TNBC). c‐Myc function and stability are considered key factors regulating chemoresistance. Recent studies have revealed a potential link between the O‐linked β‐N‐acetylglucosamine modification (O‐GlcNAcylation) of c‐Myc and its function and stability; however, the underlying mechanisms remain unexplored. This study aimed to investigate the role of O‐GlcNAcylation in promoting chemoresistance and to explore the underlying mechanisms. A cisplatin (DDP)‐resistant MDA‐MB‐231 cell line was established using a dose escalation. CCK‐8, flow cytometry, and colony formation assays were used to evaluate cell resistance under different treatments. Western blotting and coimmunoprecipitation analyses were performed to evaluate the expression of c‐Myc and its O‐GlcNAcylation under different conditions. The possible O‐GlcNAcylation sites were predicted using DictyOGlyc 1.1. Inhibition of O‐linked N‐acetylglucosamine transferase (OGT) significantly suppressed colony formation and promoted apoptosis of DDP‐resistant cells. c‐Myc expression was downregulated when OGT‐mediated O‐GlcNAcylation was inhibited. Additionally, OGT interacted with c‐Myc, promoting its stability at the Thr58 residue. Mutation of Thr58 not only resulted in lower c‐Myc stability, reduced colony formation ability, and increased apoptosis but also resulted in a decrease in both the total expression and O‐GlcNAcylation of c‐Myc. Therefore, O‐GlcNAcylation at Thr‐58 regulates c‐Myc activity to promote chemoresistance of TNBC cells.