CDT1 induces the formation of polyploid giant cancer cells and promotes centrosome amplification through the PLK4/SASS6 axis

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Polyploid giant cancer cells (PGCCs) are a unique subtype of cancer cells, characterized by distinct morphological features and a strong association with therapeutic resistance and cancer progression. Targeting PGCCs could provide novel therapeutic strategies and improve patient prognosis. However, the mechanisms underlying PGCC formation remain poorly understood, and effective therapeutic targets have not yet been fully identified. Here, we investigated the role of chromatin licensing and DNA replication factor 1 (CDT1), a vital DNA replication licensing factor, in PGCC formation. Our findings revealed that high CDT1 expression in tumors correlated with PGCC formation and poor prognosis. CDT1 overexpression significantly induced PGCC formation, enhanced cancer stemness, and promoted chromosomal instability. Interestingly, PGCCs induced by CDT1 overexpression exhibited abnormal centrosome numbers, raising questions about the role of CDT1 in centrosome duplication. We found CDT1 localized to the centrosome through its centrosomal localization signal and facilitated centrosome amplification. Notably, inhibition of the PLK4/SASS6 axis using siRNA, the selective PLK4 kinase inhibitor Centrinone, or a kinase-dead PLK4 mutant markedly suppressed centrosome amplification and PGCC formation induced by CDT1 overexpression. Moreover, we identified simvastatin as a potent inhibitor of CDT1, effectively inhibiting CDT1-mediated centrosome amplification and PGCC formation. In summary, our findings reveal a critical role for CDT1 in driving centrosome amplification and PGCC formation through activation of the PLK4/SASS6 axis, which subsequently contributes to therapeutic resistance and malignant progression. • PGCC is one of the valuable indicators for distinguishing benign from malignant tumors. • CDT1 plays a pivotal role in PGCC formation. • CDT1 localizes to the centrosome through its centrosome localization signal. • CDT1 promotes centrosome amplification and PGCC formation via the PLK4/SASS6 axis. • Simvastatin, as a potential CDT1 inhibitor, suppresses CDT1-driven PGCC formation.

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