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

• Published in: International journal of cancer Vol. 154; no. 4; pp. 723 - 737
• Main Authors: Yu, Ziqi, Dong, Xue, Song, Mei, Xu, Aizhang, He, Qing, Li, Huilin, Ouyang, Wen, Chouchane, Lotfi, Ma, Xiaojing
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 15.02.2024; Wiley Subscription Services, Inc
• Subjects: advanced breast cancer metastasis; Animals; Apoptosis; Breast cancer; Cancer; Cancer therapies; CDC73; Cell division; Cell Line, Tumor; Cell Proliferation; Doxycycline; Humans; Lung cancer; Lung Neoplasms - genetics; Lungs; Male; Mammary gland; Medical research; Metastases; Metastasis; Mice; p53; p53 Protein; Physical characteristics; Prostate cancer; RNA-mediated interference; Transcriptomes; Triple Negative Breast Neoplasms - pathology; Tumor cells; Tumor suppressor genes; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Proteins - metabolism; Tumors; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; UBR5; advanced breast cancer metastasis; apoptosis; CDC73; UBR5; p53
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.34769

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. What's new? Despite major advances in breast cancer treatment, metastatic breast cancer still has a high mortality rate. To develop better‐targeted treatments, more oncogenic targets must be identified. Here, the authors characterized the relationships between p53, CDC73 and the ubiquitin ligase UBR5, which is frequently amplified in various cancers, in post‐surgical breast cancer metastasis. They showed for the first time that UBR5 expression is required for metastatic tumor growth. Knocking down UBR5 expression in lung metastasis decreased proliferation and increased apoptosis, they found, while silencing CDC73 expression reversed these changes.