Targeting UBR5 inhibits postsurgical breast cancer lung metastases mediated by CDC73 and p53

Abstract

UBR5 is a HECT domain E3 ubiquitin ligase that is frequently amplified in breast, ovarian, and prostate cancers. Heightened UBR5 plays an oncogenic role in promoting tumor growth through immune-dependent mechanisms. However, its mode of action in driving tumor metastasis has not been definitively delineated. In this study, we used a tetracycline (Tet)-inducible RNAi-mediated expression silencing cell system to investigate how UBR5 enables postsurgical mammary tumor metastatic growth in the lungs of mice without the impact of the primary lesion. In vitro, Ubr5 knockdown induced morphological and molecular changes characteristic of epithelial-mesenchymal transition (EMT). In vivo, UBR5 promoted lung metastasis in an E3 ubiquitin ligase-dependent manner. Moreover, doxycycline-induced knockdown of UBR5 expression in metastatic cells in the lung resulted in increased apoptosis, decreased proliferation, and prolonged survival, whereas silencing the expression of cell division cycle 73 (CDC73), a tumor suppressor and an E3 ligase substrate of UBR5, reversed these effects. Transcriptome analyses revealed a prominent role for 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 and 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 unveils the novel and critical roles and relationships of UBR5, CDC73 and p53 in postsurgical breast cancer metastasis and implicates the potential of targeting this pathway in cancer therapy.