A novel UBE2T inhibitor suppresses Wnt/β-catenin signaling hyperactivation and gastric cancer progression by blocking...

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Wnt/β-catenin signaling pathway dysregulation is key in gastric cancer (GC) progression.
• Existing Wnt inhibitors show high toxicity or low efficacy in GC treatment.
• Novel therapeutic targets are needed for effective GC management.

Purpose of the Study:

• To identify novel therapeutic targets within the β-catenin destruction complex for gastric cancer.
• To investigate the role of scaffolding protein RACK1 and its regulator UBE2T in GC progression.
• To evaluate a novel UBE2T inhibitor (M435-1279) for GC treatment.

Main Methods:

• Screening of β-catenin destruction complex components in GC clinical samples.
• Identification of UBE2T as an upstream regulator of RACK1 in GC.
• Analysis of UBE2T's mechanism involving RACK1 ubiquitination and degradation.
• Assessment of UBE2T protein levels and patient prognosis.
• Evaluation of a novel UBE2T inhibitor (M435-1279) in preclinical models.

Main Results:

• RACK1 deficiency, not APC, AXIN, or GSK3β, is significantly linked to GC progression.
• UBE2T promotes GC by hyperactivating Wnt/β-catenin signaling via RACK1 ubiquitination and degradation at specific lysine residues.
• Higher UBE2T levels correlate with poorer prognosis in GC patients.
• The novel inhibitor M435-1279 effectively suppresses GC progression by blocking UBE2T-mediated RACK1 degradation.
• M435-1279 demonstrates a favorable balance of growth inhibition and reduced cytotoxicity.

Conclusions:

• UBE2T promotes gastric cancer progression through RACK1 ubiquitination, making it a promising therapeutic target.
• The novel inhibitor M435-1279 offers a targeted approach for GC treatment with improved safety profile.
• This study provides a new therapeutic strategy for GC patients with aberrant Wnt/β-catenin signaling.