UBR5 targets tumor suppressor CDC73 proteolytically to promote aggressive breast cancer

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 beta-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 Lys(243), Lys(247), and Lys(257) in a non-canonical manner that is dependent on the non-phosphorylation state of CDC73 at Ser(465). 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.

Automated summary

This study reveals that CDC73, a substrate of UBR5, plays a crucial role in inhibiting tumor growth and metastasis in triple-negative breast cancer (TNBC) and is negatively associated with breast cancer progression. Destabilizing CDC73 through polyubiquitination provides a potential approach to suppress the pro-tumor activities of UBR5.