Tumor cell dissemination in cancer patients is associated with a significant reduction in their survival and quality of life. The ubiquitination pathway plays a fundamental role in the maintenance of protein homeostasis both in normal and stressed conditions and its dysregulation has been associated with malignant transformation and invasive potential of tumor cells, thus highlighting its value as a potential therapeutic target. In order to identify novel molecular targets of tumor cell migration and invasion we performed a genetic screen with an shRNA library against ubiquitination pathway-related genes. To this end, we set up a protocol to specifically enrich positive migration regulator candidates. We identified the deubiquitinase USP19 and demonstrated that its silencing reduces the migratory and invasive potential of highly invasive breast cancer cell lines. We extended our investigation in vivo and confirmed that mice injected with USP19 depleted cells display increased tumor-free survival, as well as a delay in the onset of the tumor formation and a significant reduction in the appearance of metastatic foci, indicating that tumor cell invasion and dissemination is impaired. In contrast, overexpression of USP19 increased cell invasiveness both in vitro and in vivo, further validating our findings. More importantly, we demonstrated that USP19 catalytic activity is important for the control of tumor cell migration and invasion, and that its molecular mechanism of action involves LRP6, a Wnt co-receptor. Finally, we showed that USP19 overexpression is a surrogate prognostic marker of distant relapse in patients with early breast cancer. Altogether, these findings demonstrate that USP19 might represent a novel therapeutic target in breast cancer.

癌症患者中的肿瘤细胞传播与其生存率和生活质量的显着降低有关。泛素化途径在维持正常和应激条件下的蛋白质稳态中起着重要作用，其失调与肿瘤细胞的恶性转化和侵袭潜能有关，因此突出了其作为潜在治疗靶点的价值。为了确定肿瘤细胞迁移和侵袭的新分子靶标，我们使用 shRNA 文库针对泛素化途径相关基因进行了遗传筛选。为此，我们建立了一个协议来专门丰富积极的移民监管机构候选人。我们鉴定了去泛素化酶 USP19，并证明其沉默可降低高侵袭性乳腺癌细胞系的迁移和侵袭潜力。我们扩展了我们的体内研究，并证实注射 USP19 耗尽细胞的小鼠表现出更高的无肿瘤存活率，以及肿瘤形成的延迟和转移灶出现的显着减少，表明肿瘤细胞侵袭和传播受到损害。相反，USP19 的过表达增加了体外和体内的细胞侵袭性，进一步验证了我们的发现。更重要的是，我们证明了 USP19 催化活性对于控制肿瘤细胞迁移和侵袭很重要，并且其分子作用机制涉及 LRP6，一种 Wnt 辅助受体。最后，我们发现 USP19 过度表达是早期乳腺癌患者远处复发的替代预后标志物。总而言之，这些发现表明 USP19 可能代表乳腺癌的新治疗靶点。