Journal Article

YY2/BUB3 Axis promotes SAC Hyperactivation and Inhibits Colorectal Cancer Progression via Regulating Chromosomal Instability

Shourong Wu, Mankun Wei, Makoto Miyagishi, Hezhao Zhao, Rendy Hosea, Vivi Kasim, Wenfang Li, Sharon Hillary, Wei Duan, Ian Timothy Sembiring Meliala

2024

Overview

Spindle assembly checkpoint (SAC) is a crucial safeguard mechanism of mitosis fidelity that ensures 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 therapeutic response and prognosis. However, the mechanism by which CIN determines tumor cell survival and therapeutic response remains poorly understood. Here, using a cross‐omics approach, YY2 is identified as a mitotic regulator that promotes SAC activity by activating the transcription of budding uninhibited by benzimidazole 3 (BUB3), a component of SAC. While both conditions induce CIN, a defect in YY2/SAC activity enhances mitosis and tumor growth. Meanwhile, hyperactivation of SAC mediated by YY2/BUB3 triggers a delay in mitosis and suppresses growth. Furthermore, it is revealed that YY2/BUB3‐mediated excessive CIN causes higher cell death rates and drug sensitivity, whereas residual tumor cells that survived DNA damage‐based therapy have moderate CIN and increased drug resistance. These results provide insights into the role of SAC activity and CIN levels in influencing tumor cell survival and drug response, as well as suggest a novel anti‐tumor therapeutic strategy that combines SAC activity modulators and DNA‐damage agents. CIN is a hallmark of cancer and can drive tumorigenesis; paradoxically, high CIN correlates with better prognosis in clinical patients. The underlying cause of this paradox is still unclear. This study identifies the novel role of YY2 in modulating BUB3‐mediated SAC activity and CIN, as well as YY2/BUB3‐mediated SAC activity and CIN levels role in determining tumor cell fates.

• Publisher: Wiley,John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Animals / Cell cycle / Cell Cycle Proteins - genetics / Cell Cycle Proteins - metabolism / Cell division / Cell Line, Tumor / chromosomal instability (CIN) / Chromosomal Instability - genetics / Colorectal cancer / Colorectal Neoplasms - genetics / Colorectal Neoplasms - metabolism / Colorectal Neoplasms - pathology / Disease Models, Animal / Disease Progression / DNA damage / drug resistance / Genes / Humans / M Phase Cell Cycle Checkpoints - genetics / Medical prognosis / Mice / mitosis / Q / Research Article / residual tumor cells / Science / Tumorigenesis / Variance analysis / yin yang 2 (YY2)