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

The C-terminus of Hsc70-interacting protein (CHIP), an E3 ubiquitin ligase, plays a pivotal role in cellular protein homeostasis by targeting client proteins for proteasomal degradation. DEAD-box RNA helicase DDX17 is a key regulator of RNA metabolism and has been implicated in various cancer-related processes, including Wnt/β-catenin signalling and EMT. In this study, we uncover a novel regulatory axis involving CHIP and DDX17 responsible for modulation of Wnt/β-catenin signalling in colorectal cancer (CRC). Bioinformatic analyses of CPTAC database and immunohistochemical analysis of clinical samples revealed a significant negative correlation between CHIP and DDX17. By using immunoprecipitation-mass spectrometry we have identified DDX17 as a high-confidence interacting partner of CHIP, which was validated through co-immunoprecipitation, domain-mapping, immunocytochemistry, and molecular docking studies, pinpointing the TPR domain of CHIP is essential for this interaction. Mechanistically, CHIP overexpression led to accelerated degradation of DDX17, resulting in reduced β-catenin mRNA stability, leading to the suppression of Wnt/β-catenin signalling that results in G1 arrest and decreasing proliferation and EMT. Conversely, CHIP knockdown stabilized DDX17, hence promoting β-catenin signalling that leads to oncogenic phenotype. Our results suggest that CHIP exerts a tumor-suppressive phenotype in CRC by destruction of DDX17, thereby attenuating β-catenin-driven oncogenic processes. Altogether, this study identifies a novel "CHIP-DDX17-β-catenin" axis as a critical regulatory mechanism in CRC.