2. Academic Validation
  3. UBR5 targets tumor suppressor CDC73 proteolytically to promote aggressive breast cancer

UBR5 targets tumor suppressor CDC73 proteolytically to promote aggressive breast cancer

  • Cell Death Dis. 2022 May 12;13(5):451. doi: 10.1038/s41419-022-04914-6.
Gang Xiang 1,  Shuxuan Wang 1,  Ling Chen 1,  Mei Song 2,  Xiaoxu Song 1,  Huan Wang 1,  Pengbo Zhou 3,  Xiaojing Ma 4,  Jing Yu 5
Affiliations

Affiliations

  • 1 Joint International Research Laboratory of Metabolic and Developmental Sciences, Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China.
  • 2 Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, 10065, USA.
  • 3 Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA.
  • 4 Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, 10065, USA. [email protected].
  • 5 Joint International Research Laboratory of Metabolic and Developmental Sciences, Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China. [email protected].
PMID: 35551175 DOI: 10.1038/s41419-022-04914-6
Abstract

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.

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