TRIM58 inactivates p53/p21 to promote chemoresistance via ubiquitination of DDX3 in breast cancer

Chemotherapy resistance is that the most important reason behind of carcinoma treatment failure but the underlying molecular mechanisms are unclear. Members of the tripartite motif containing protein (TRIM) family play crucial roles in the carcinogenesis and development of resistance against chemotherapy. Herein, we first confirmed that TRIM58 is highly expressed in triple-negative breast cancer tissues and drug-resistant MCF7/ADR cells. Furthermore, TRIM58 knockdown resulted in increased sensitivity of MCF7/ADR cells toward doxorubicin in vitro and in vivo. In contrast, TRIM58 overexpression in breast cancer cells increased doxorubicin resistance. TRIM58 was found to interact with DDX3, a protein recently reported to modulate resistance against chemotherapy. We found that TRIM58 negatively regulates DDX3 expression downstream of the P53/P21 pathway, and that DDX3 is degraded by TRIM58-mediated ubiquitination. Knockdown of DDX3 reversed doxorubicin chemotherapy sensitivity induced by TRIM58 knockdown via the P53/P21 pathway.Our study reveals that TRIM58 mediates a novel mechanism underlying the development of resistance against chemotherapy in breast cancer and provides potential targets for developing novel therapeutic targets for breast cancer.