UBR5 targets tumor suppressor CDC73 proteolytically to promote aggressive breast cancer

Area of Science:

• Molecular Oncology
• Cancer Biology
• Ubiquitin Ligase Function

Background:

• UBR5, a HECT-domain E3 ubiquitin ligase, is implicated in aggressive breast cancers.
• Identifying UBR5 substrates is critical for understanding its role and developing targeted therapies.
• Triple-negative breast cancer (TNBC) presents a significant therapeutic challenge.

Purpose of the Study:

• To identify key substrates of UBR5 that regulate its tumorigenic and metastatic activities.
• To elucidate the mechanism by which UBR5 exerts its pro-tumorigenic effects in TNBC.
• To explore the therapeutic potential of targeting the UBR5-CDC73 interaction.

Main Methods:

• Investigated CDC73 as a substrate of UBR5.
• Analyzed the impact of CDC73 on UBR5-mediated regulation of β-catenin, E-cadherin, apoptosis, and CD8+ T cell infiltration.
• Examined the polyubiquitination sites and phosphorylation status of CDC73.
• Correlated CDC73 expression with breast cancer patient progression.

Main Results:

• CDC73 was identified as a key substrate that antagonizes UBR5's tumorigenic and metastatic functions in TNBC.
• UBR5 destabilizes CDC73 via non-canonical polyubiquitination at specific lysine residues (Lys243, Lys247, Lys257), dependent on the non-phosphorylated state of CDC73 at Ser465.
• CDC73 expression is inversely associated with breast cancer progression.
• Modulation of CDC73 impacts tumor cell apoptosis and CD8+ T cell infiltration.

Conclusions:

• CDC73 acts as a crucial regulator, limiting UBR5's pro-tumor activities in breast cancer.
• The UBR5-CDC73 interaction represents a potential therapeutic target for breast cancer interventions.
• CDC73 may function as a molecular switch controlling UBR5's oncogenic functions.