XRCC4 glutarylation increases sensitivity to PARP inhibitors in breast cancer by inhibiting mTOR activity and promoting autophagy

Background Glutarylation, a newly identified form of protein acylation, has been linked to the regulation of tumor metabolism. However, the role of glutarylation in breast cancer is currently unclear. Methods Multi-omics datasets analysis was employed to delineate the characteristics of XRCC4 in breast cancer. The roles of XRCC4 in breast cancer were validated using CCK-8, EdU, and colony formation assays. The glutarylation of XRCC4 was confirmed through bioinformatics predictions, immunofluorescence, and Co-IP experiments. Results In this study, we observed that the upregulation of XRCC4 was associated with a poor prognosis in patients with breast cancer. In vitro experiments showed that XRCC4 overexpression promoted the proliferation of breast cancer cells, whereas XRCC4 knockdown inhibited cell proliferation. Mechanistic analysis revealed that the XRCC4 protein can be glutarylated. Specifically, our findings showed that the deglutarylase SIRT5 binds to XRCC4 in the cytoplasm, promoting its expression at the protein level. Knockdown of XRCC4 promotes autophagic cell death by inhibiting the p-mTOR/p-ULK1 pathway. Conclusion XRCC4 glutarylation enhances the sensitivity of breast cancer to PARP inhibitors through the inhibition of mTOR activity and the promotion of autophagy, thereby offering additional options for maintenance therapy utilizing PARP inhibitors in breast cancer treatment.