CENP-A in cancer: from centromere identity to genome instability

Chromatin organization plays a fundamental role in the regulation and preservation of the eukaryotic genome. Histone variants contribute to chromatin dynamics by replacing canonical histones within nucleosomes and conferring specialized structural and regulatory properties. Among these variants, the centromere-specific histone H3 variant CENP-A is essential for establishing and maintaining centromere identity and ensuring accurate chromosome segregation during mitosis. Proper expression, deposition, and maintenance of CENP-A are tightly regulated through dedicated chaperones and mechanisms. Disruption of these regulatory processes can lead to aberrant CENP-A expression or mislocalization, resulting in defective centromere function and chromosome segregation. CENP-A is frequently overexpressed in several human cancers and CENP-A overexpression often correlates with tumor progression, chromosomal instability, and poor prognosis. Ectopic incorporation of CENP-A into non-centromeric chromatin can promote aberrant chromatin states and partial recruitment of kinetochore components. These alterations can disrupt normal kinetochore function and contribute to chromosome missegregation, thereby promoting chromosomal instability (CIN) and tumor evolution. In addition to its role in mitotic fidelity, emerging studies suggest that ectopic CENP-A can interfere with chromatin factors and influence transcriptional regulation. Hence, CENP-A emerges as a potential biomarker for cancer prognosis and therapeutic response. In this review, we summarize current knowledge on the regulation of CENP-A expression and deposition, discuss the functional consequences of its dysregulation in cancer, and highlight emerging clinical and translational implications of targeting centromere chromatin pathways in oncology.