CHIP modulates Wnt/β-catenin signalling in colorectal cancer through proteasomal degradation of DDX17

Area of Science:

• Molecular Biology
• Oncology
• Cellular Biology

Background:

• CHIP (C-terminus of Hsc70-interacting protein) is an E3 ubiquitin ligase critical for protein homeostasis.
• DDX17, a DEAD-box RNA helicase, regulates RNA metabolism and is involved in cancer processes like Wnt/β-catenin signaling and EMT.
• Dysregulation of these pathways is implicated in colorectal cancer (CRC) development.

Purpose of the Study:

• To investigate the novel regulatory role of CHIP and DDX17 in colorectal cancer.
• To elucidate the mechanism by which CHIP and DDX17 interact and influence Wnt/β-catenin signaling.
• To identify the CHIP-DDX17-β-catenin axis as a potential therapeutic target in CRC.

Main Methods:

• Bioinformatic analysis of the CPTAC database.
• Immunohistochemical analysis of clinical CRC samples.
• Immunoprecipitation-mass spectrometry and co-immunoprecipitation assays to confirm protein interactions.
• Domain-mapping, immunocytochemistry, and molecular docking to identify the interaction interface.
• Assessment of cell cycle arrest, proliferation, and EMT markers upon CHIP modulation.

Main Results:

• A significant negative correlation was observed between CHIP and DDX17 expression in CRC.
• DDX17 was identified as a high-confidence interacting partner of CHIP, with the TPR domain of CHIP being essential for this interaction.
• CHIP overexpression accelerated DDX17 degradation, suppressed Wnt/β-catenin signaling, reduced proliferation, and inhibited EMT.
• CHIP knockdown led to DDX17 stabilization, enhanced Wnt/β-catenin signaling, and promoted an oncogenic phenotype.

Conclusions:

• CHIP acts as a tumor suppressor in CRC by promoting DDX17 degradation.
• The novel CHIP-DDX17-β-catenin axis is a critical regulatory mechanism in colorectal cancer.
• Targeting this axis may offer a new therapeutic strategy for CRC treatment.