SPOP targets oncogenic protein ZBTB3 for destruction to suppress endometrial cancer

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Dysregulation of the ubiquitin-proteasome pathway is linked to cancer.
• SPOP, a key component of E3 ubiquitin ligase complexes, is frequently mutated in endometrial cancers (ECs).
• The precise role of SPOP mutations in EC pathogenesis is unclear.

Purpose of the Study:

• To investigate the function of SPOP in EC.
• To identify SPOP substrates and understand the impact of SPOP mutations on EC cell behavior.
• To explore potential therapeutic strategies for SPOP-mutated EC.

Main Methods:

• Identified ZBTB3 as a substrate of the SPOP-CUL3-RBX1 E3 ubiquitin ligase complex.
• Analyzed the effect of wild-type SPOP and EC-associated SPOP mutants on ZBTB3 stability.
• Assessed the impact of SPOP inactivation on endometrial cell proliferation, migration, and invasion.
• Investigated the role of ZBTB3 and Sonic hedgehog (SHH) signaling in SPOP-mutated EC.
• Evaluated the efficacy of the SHH inhibitor RUSKI-43 in preclinical models.

Main Results:

• SPOP specifically targets ZBTB3 for degradation via the ubiquitin-proteasome pathway.
• EC-associated SPOP mutants exhibit impaired ZBTB3 degradation, leading to ZBTB3 accumulation.
• SPOP inactivation promotes EC cell proliferation, migration, and invasion, partly due to ZBTB3 accumulation.
• SPOP inactivation results in ZBTB3-dependent upregulation of SHH signaling in EC cells.
• SHH inhibition with RUSKI-43 suppresses proliferation, migration, and invasion in SPOP-altered EC cells.

Conclusions:

• SPOP mutations contribute to EC progression by disrupting ZBTB3 degradation and upregulating SHH signaling.
• Targeting SHH signaling represents a potential therapeutic approach for patients with SPOP-mutated endometrial cancer.