Identifying Cell Cycle Modulators That Selectively Target ARIDIA Deficiency Using High-Throughput Image-Based Screening

ARIDIA, a component of the chromatin remodeling complex SWI/SNF, is an evolutionarily conserved complex that uses the energy of adenosine triphosphate hydrolysis to remodel chromatin structure and functions as a master regulator of gene transcription. Recent genomic studies have revealed that ARIDIA is one of the most frequently mutated genes in human cancers. However, therapeutic approaches that selectively target ARIDIA-mutant tumors are not yet clinically available. Our previous study showed that ARIDIA facilitates chromatin response and cell cycle checkpoint activation after DNA damage. Therefore, an ARIDIA deficiency may result in therapeutic vulnerabilities in cell cycle modulators. The goals of our study were to develop a novel screening approach, based on fluorescent ubiquitination-based cell cycle indicators (FUCCI), and to identify chemical agents that can selectively modulate the cell cycle transition in ARIDIA-deficient cancer cells. Using this high-throughput assay, we screened 2643 compounds and identified six potential chemical modulators that can selectively modulate the cell cycle in ARIDIA-deficient cells; these agents may be useful for developing new therapeutics for ARIDIA-mutant tumors. In summary, our study demonstrates that FUCCI cell-based high-content screening is a powerful and effective approach for identifying cell cycle modulators and can be applied to multigenotypic screening for targeted cancer therapeutics.