USP53 Exerts Tumor-Promoting Effects in Triple-Negative Breast Cancer by Deubiquitinating CRKL

SIMPLE SUMMARY: Triple-negative breast cancer (TNBC) has a high recurrence rate and metastasis rate, and the prognosis for patients is poor. Identifying novel treatment avenues for TNBC is crucial for the treatment and prognosis of TNBC patients. Deubiquitinase deficiency is associated with the occurrence and progression of several diseases, including cancer. As a member of deubiquitinase, ubiquitin-specific peptidase 53 (USP53) is essential for the development of tumors such as hepatocellular carcinoma and renal clear cell carcinoma. However, the precise function of USP53 in TNBC remains unknown. Our study has identified USP53 as a molecular target that mediates the progression of TNBC. This not only deepens our understanding of the tumorigenesis and development of TNBC, but also provides new potential therapeutic targets for TNBC patients. ABSTRACT: Breast cancer (BC) ranks in the top five malignant tumors in terms of morbidity and mortality rates. Among BC subtypes, TNBC has a high recurrence rate and metastasis rate and the worst prognosis. However, the exact mechanism by which TNBC develops is unclear. Here, we show that the deubiquitinase USP53 contributes to tumor growth and metastasis in TNBC. USP53 is overexpressed in TNBC, and this phenotype is linked to a poor prognosis. Functionally, USP53 promotes TNBC cell proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT). More importantly, USP53 decreases the chemosensitivity of BC cells by enhancing v-crk sarcoma virus CT10 oncogene homologue (avian)-like (CRKL) expression. Mechanistically, USP53 directly binds CRKL to stabilize and deubiquitinate it, thereby preventing CRKL degradation. Overall, we discovered that USP53 deubiquitinates CRKL, encourages tumor development and metastasis, and reduces chemosensitivity in TNBC. These findings imply that USP53 might represent a new therapeutic target for the treatment of TNBC.