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 motifcontaining protein (TRIM) family play crucial roles in the carcinogenesis and development of resistance against chemothe...

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Bibliographic Details
Published in:The international journal of biochemistry & cell biology 2022-02, Vol.143, p.106140-106140, Article 106140
Main Authors: Wang, Juan, Yang, Fan, Zhuang, Jialang, Huo, Qin, Li, Jiaying, Xie, Ni
Format: Article
Language:English
Subjects:
Animals
breast neoplasms
Breast Neoplasms - genetics
Breast Neoplasms - pathology
carcinogenesis
carcinoma
Cell Line, Tumor
Chemotherapy
DEAD-box RNA Helicases - metabolism
Doxorubicin
drug resistance
drug therapy
Female
Humans
Mice
Mice, Nude
Transfection
Treatment resistance
Tumor Suppressor Protein p53 - metabolism
Ubiquitination
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Summary:Chemotherapy resistance is that the most important reason behind of carcinoma treatment failure but the underlying molecular mechanisms are unclear. Members of the tripartite motifcontaining 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.
ISSN:1357-2725
1878-5875
DOI:10.1016/j.biocel.2021.106140