Targeting TRIM15-mediated Axin1 depolymerization suppresses Wnt signaling and inhibits colorectal cancer growth

Area of Science:

• Molecular Biology
• Oncology
• Cell Signaling

Background:

• Axin1 is crucial for Wnt/β-catenin signaling and cancer progression.
• Axin1 polymerization is essential for the β-catenin destruction complex.
• Mechanisms regulating Axin1 polymerization are not fully understood.

Purpose of the Study:

• To investigate the role of TRIM15 in regulating Axin1 polymerization.
• To elucidate the impact of TRIM15 on Wnt signaling and colorectal cancer.
• To explore TRIM15 as a potential therapeutic target for colorectal cancer.

Main Methods:

• Investigated TRIM15 interaction with Axin1 using its coiled-coil domain.
• Manipulated TRIM15 expression to assess effects on Wnt signaling, cell proliferation, and tumor growth.
• Utilized mouse models (AOM/DSS and Apc^Min/+) for genetic ablation studies of Trim15.

Main Results:

• TRIM15 was found to interfere with Axin1 polymerization, promoting Wnt activation and colorectal cancer growth.
• Reduced TRIM15 expression significantly inhibited Wnt signaling, cell proliferation, and tumor growth.
• Genetic ablation of Trim15 suppressed tumor formation in mouse models.
• TRIM15 acts as a Wnt target gene, forming a positive feedback loop in colon cancer.
• TRIM15 is highly expressed in colorectal cancer and positively correlates with β-catenin.
• Increased Axin1 levels and polymerization synergistically induce apoptosis.

Conclusions:

• TRIM15 negatively regulates Axin1 polymerization, thereby promoting Wnt signaling and colorectal cancer.
• Targeting TRIM15 presents a potential therapeutic strategy for colorectal cancer by modulating Wnt signaling.
• TRIM15 is a novel regulator of Axin1 polymerization and a potential biomarker in colorectal cancer.