UBR5 targets tumor suppressor CDC73 proteolytically to promote aggressive breast cancer.

TitleUBR5 targets tumor suppressor CDC73 proteolytically to promote aggressive breast cancer.
Publication TypeJournal Article
Year of Publication2022
AuthorsXiang G, Wang S, Chen L, Song M, Song X, Wang H, Zhou P, Ma X, Yu J
JournalCell Death Dis
Date Published2022 May 12
KeywordsBreast, Cell Line, Tumor, Humans, Transcription Factors, Triple Negative Breast Neoplasms, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Ubiquitination

UBR5, a HECT-domain E3 ubiquitin ligase, is an attractive therapeutic target for aggressive breast cancers. Defining the substrates of UBR5 is crucial for scientific understanding and clinical intervention. Here, we demonstrate that CDC73, a component of the RNA polymerase II-associated factor 1 complex, is a key substrate that impedes UBR5's profound tumorigenic and metastatic activities in triple-negative breast cancer (TNBC) via mechanisms of regulating the expression of β-catenin and E-cadherin, tumor cell apoptosis and CD8+ T cell infiltration. Expression of CDC73 is also negatively associated with the progression of breast cancer patients. Moreover, we show that UBR5 destabilizes CDC73 by polyubiquitination at Lys243, Lys247, and Lys257 in a non-canonical manner that is dependent on the non-phosphorylation state of CDC73 at Ser465. CDC73 could serve as a molecular switch to modulate UBR5's pro-tumor activities and may provide a potential approach to developing breast cancer therapeutic interventions.

Alternate JournalCell Death Dis
PubMed ID35551175
PubMed Central IDPMC9098409
Grant ListR01 CA213992 / CA / NCI NIH HHS / United States
Related Faculty: 
Pengbo Zhou, Ph.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
Surgical Pathology: (212) 746-2700