Chromosomal instability (CIN) plays a central role in cancer progression by promoting tumour evolution, metastasis, and treatment resistance. Defects in mitosis and cytokinesis are known contributors to CIN. Moreover, our data suggest that these processes are critically regulated by the Y-box binding protein-1 (YB-1). Despite YB-1 expression being clinically associated with poor prognosis, its role in promoting CIN and thereby contributing to aggressive disease, remains unclear.
We hypothesise that sustained YB-1 overexpression promotes CIN through successive cell divisions, driving tumour evolution. Our pan-cancer dataset analysis revealed a strong association between high YB-1 mRNA expression, increased genomic instability, and reduced disease-free survival. To explore this, we engineered H1299 lung cancer cells with tetracycline-inducible YB-1 expression. After 21 days of continuous induction, YB-1-overexpressing clones displayed altered growth dynamics, initially reduced, followed by accelerated proliferation, suggestive of clonal selection. Whole genome sequencing analysis revealed distinct chromosomal alterations, while live-cell imaging identified features of CIN, including micronuclei, multinucleation, and prolonged mitosis. We are currently evaluating the functional consequences of prolonged YB-1 overexpression.
Collectively, our data identifies, for the first time, a direct mechanistic link between YB-1 overexpression and CIN, establishing YB-1 as a key driver of tumour evolution and a promising therapeutic target.