Deletion of the Mis12C-Binding Domain of CENP-C Promotes Chromosomal Aneuploidy in Cutaneous Squamous Cell Carcinoma.

Abstract

CENP-C, an essential component of the kinetochore, connects centromeric chromatin to the outer kinetochore, and thereby ensures accurate chromosome segregation. Although deletion of the Mis12-binding domain (M12BD) of CENP-C does not cause developmental disorders in mice, it promotes malignant tumor progression in the two-stage DMBA/TPA-induced skin carcinogenesis model. In this study, we have demonstrated that M12BD deletion of CENP-C enhances proliferation and then promotes abnormal differentiation in DMBA/TPA-induced carcinomas in mice. To elucidate the underlying molecular mechanisms, we performed RNA sequencing and found the dysregulated expression of keratinization-related genes. Intriguingly, elevated chromosomal aneuploidy was detectable in mice with the M12BD deletion of CENP-C. Among the aneuploidies, trisomies of chromosomes 6 and 10 took place at the highest frequency. These specific chromosomal gains were accompanied by upregulation of genes involved in immune and inflammatory responses. Together, our present findings strongly suggest that M12BD of CENP-C plays a critical role in the regulation of epithelial differentiation during tumor development in mice.