CCT5 maintains mitotic fidelity and promotes early colorectal tumorigenesis.

Colorectal cancer (CRC) is a leading cause of cancer-related mortality, and early tumorigenesis is closely associated with mitotic dysregulation and chromosomal instability. To define molecular mechanisms supporting mitotic fidelity during CRC initiation, we combined multi-omics profiling, genetically engineered mouse models, and functional assays to examine the role of the chaperonin subunit CCT5. Transcriptomic and proteomic analyses revealed elevated CCT5 expression in stage I CRC and precancerous lesions, indicating diagnostic relevance. The genetic depletion of CCT5 suppressed epithelial proliferation, reduced dysplastic transformation, and limited tumor initiation in vivo. In CRC cells, CCT5 silencing impaired proliferation and induced G2/M arrest. Mechanistically, CCT5 interacts with CDC20 and facilitates turnover of the MCC-CDC20-APC/C complex, enabling metaphase-to-anaphase progression. These findings position CCT5 as a regulator of early CRC development with implications for early detection and therapeutic intervention.