文章：

USP53通过去泛素化CRKL在三阴性乳腺癌中发挥促癌作用

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

原文发布日期：18 October 2023

DOI: 10.3390/cancers15205033

类型: Article

开放获取: 是

英文摘要：

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.

摘要翻译： 

乳腺癌在发病率和死亡率方面均位列前五大恶性肿瘤。在乳腺癌亚型中，三阴性乳腺癌具有高复发率、高转移率及最差的预后特征，但其确切发病机制尚未明确。本研究发现去泛素化酶USP53在三阴性乳腺癌的肿瘤生长与转移过程中发挥重要作用。USP53在三阴性乳腺癌中呈现过表达现象，且该表型与不良预后密切相关。功能实验表明，USP53能促进三阴性乳腺癌细胞的增殖、迁移、侵袭及上皮-间质转化过程。更重要的是，USP53通过增强v-crk肉瘤病毒CT10癌基因同源物（禽类）样蛋白表达，降低了乳腺癌细胞的化疗敏感性。机制研究揭示，USP53可直接结合CRKL蛋白，通过去泛素化作用稳定CRKL蛋白水平，从而阻止其降解。综上所述，本研究首次阐明USP53通过去泛素化修饰CRKL蛋白，促进三阴性乳腺癌的肿瘤进展与转移，并降低其化疗敏感性。这些发现提示USP53可能成为治疗三阴性乳腺癌的新潜在治疗靶点。

原文链接：

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