PDF(Pubmed)
Abstract：
UBR5 is a HECT domain E3 ubiquitin ligase that is frequently amplified in breast, ovarian and prostate cancers. Heightened UBR5 expression plays a profound role in tumor growth through immune-dependent mechanisms; however, its mode of action in driving tumor metastasis has not been definitively delineated. Herein, we used a tetracycline (Tet)-inducible RNAi-mediated expression silencing cell system to investigate how UBR5 enables postsurgical mammary tumor metastatic growth in mouse lungs without the continuous influence of the primary lesion. In vitro, Ubr5 knockdown induces morphological and molecular changes characteristic of epithelial-mesenchymal transition (EMT). In vivo, UBR5 promotes lung metastasis in an E3 ubiquitin ligase-dependent manner. Moreover, doxycycline-induced UBR5 expression knockdown in metastatic cells in the lungs, following removing the primary tumors, resulted in increased apoptosis, decreased proliferation and prolonged survival, whereas silencing the expression of cell division cycle 73 (CDC73), a tumor suppressor and E3 ligase substrate of UBR5, reversed these effects. Transcriptome analyses revealed a prominent role of the p53 pathway in dovitinib-induced apoptosis of tumor cells differentially regulated by UBR5 and CDC73. In human triple-negative breast cancer (TNBC) patient specimens, a strong inverse correlation was observed between UBR5 and CDC73 protein levels, with reduced CDC73 expression at metastatic sites compared to primary lesions. Furthermore, a xenograft model of human TNBC recapitulated the metastatic properties and characteristics of the unique UBR5-CDC73 functional antagonism. This study reveals the novel and critical roles and intricate relationships of UBR5, CDC73 and p53 in postsurgical breast cancer metastasis and indicates the potential of targeting this pathway in cancer therapy.
摘要：
UBR5是HECT域E3泛素连接酶，经常在乳腺中扩增，卵巢癌和前列腺癌。UBR5的表达通过免疫依赖性机制在肿瘤生长中起着深远的作用；然而，其驱动肿瘤转移的作用方式尚未明确描述。在这里，我们使用四环素(Tet)诱导的RNAi介导的表达沉默细胞系统来研究UBR5如何使小鼠肺中的术后乳腺肿瘤转移生长,而不会受到原发灶的持续影响.体外，Ubr5敲低诱导上皮-间质转化（EMT）的形态学和分子改变。在体内,UBR5以E3泛素连接酶依赖性方式促进肺转移。此外，多西环素诱导的UBR5在肺转移细胞中的表达敲低，切除原发肿瘤后，导致细胞凋亡增加，减少增殖和延长生存期，而沉默细胞分裂周期73（CDC73）的表达，肿瘤抑制因子和UBR5的E3连接酶底物逆转了这些作用。转录组分析显示p53通路在多替尼诱导的由UBR5和CDC73差异调节的肿瘤细胞凋亡中的重要作用。在人类三阴性乳腺癌（TNBC）患者标本中，在UBR5和CDC73蛋白水平之间观察到强烈的负相关，与原发性病变相比，转移部位的CDC73表达减少。此外，人TNBC的异种移植模型概括了独特的UBR5-CDC73功能拮抗作用的转移特性和特征。这项研究揭示了UBR5，CDC73和p53在术后乳腺癌转移中的新颖和关键的作用和复杂的关系，并表明了在癌症治疗中靶向该途径的潜力。
