Targeting Cytokinesis Bridge Proteins to Kill High-CIN Type Tumors

ABSTRACT As a common feature of tumors, chromosomal instability (CIN) not only forces carcinomatous evolution, but also loads cancer cells with extra pressure through a robust imbalance of genome patterning that may be used for cancer treatment. Errors in cytokinesis increase CIN, so cytokinesis components are valuable targets for treating cancer. However, due to the short time span and confined space of cytokinesis bridges, profiling cytokinesis factors is challenging. Taking advantage of engineered ascorbate peroxidase (APEX2), we established a cytokinesis bridge-APEX reaction in living cells. A total of 218 cytokinesis bridge proteins were identified with high reliability. Knockdown of cytokinesis bridge genes generated micronuclei that activate the cGAS-pathway and cause apoptosis in cancer cells bearing high CIN rather than low CIN. Thus, our study proposes a strategy for killing high-CIN tumors regardless of tumor type, and provides a proteome resource of cytokinetic bridges for future research.