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 <i>in vivo</i>. 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.