YY2/BUB3 axis-mediated SAC hyperactivity determines tumor cell fate through chromosomal instability

Abstract

AbstractSpindle assembly checkpoint (SAC) is a crucial safeguard mechanism of mitosis fidelity, which is fundamental for equal division of duplicated chromosomes to the two progeny cells. Impaired SAC can lead to chromosomal instability (CIN), a well-recognized hallmark of cancer that facilitates tumor progression; paradoxically, high CIN levels are associated with better drug sensitivity and prognosis. However, the mechanism by which CIN determines tumor cell fates and drug sensitivity remain poorly understood. In this study, using a cross-omics approach, we identified YY2 as a mitotic regulator that peaks at M phase and promotes SAC activity by positively regulating the transcriptional activity ofbudding uninhibited by benzimidazole 3(BUB3), a component of SAC. While inducing CIN, YY2/SAC activity defect enhanced mitosis and tumor growth, whereas YY2/SAC hyperactivation, as a result ofYY2overexpression, triggered mitotic delay and growth suppression. Furthermore, we revealed that excessive CIN, caused by eitherYY2overexpression or further inhibiting SAC activity inYY2-knocked out cells, leads to higher cell death rates. However, residual tumor cells that survived DNA damage-based therapy had moderate CIN and increased drug resistance; meanwhileYY2overexpression in these cells sensitizes them to DNA-damage agents. Hence, this study provides insights into the regulatory mechanism of SAC activity as well as the role of YY2/BUB3 axis, SAC activity, and CIN levels in determining tumor cell fate. Furthermore, this study also links up tumor cells drug resistance with moderate CIN, and suggest a novel anti-tumor therapeutic strategy that combines SAC activity modulators and DNA-damage agents.SignificanceThis study identifies the novel role of YY2/BUB3 axis as a SAC modulator, as well as emphasizing the role of YY2-mediated SAC activity and CIN levels in determining tumor cell fates.