title: Identifying Cell Cycle Modulators That Selectively Target ARID1A Deficiency Using High-Throughput Image-Based Screening.
abstract: ARID1A, 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 ARID1A is one of the most frequently mutated genes in human cancers. However, therapeutic approaches that selectively target ARID1A-mutant tumors are not yet clinically available. Our previous study showed that ARID1A facilitates chromatin response and cell cycle checkpoint activation after DNA damage. Therefore, an ARID1A 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 ARID1A-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 ARID1A-deficient cells; these agents may be useful for developing new therapeutics for ARID1A-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.
authors.affiliation: 1 Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China.|2 Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Lihong
authors.initials: L
authors.lastname: Zhang
authors.affiliation: 2 Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Shen
authors.affiliation: 2 Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|3 Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Yin
authors.affiliation: 2 Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Peng
authors.affiliation: 2 Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Lulu
authors.initials: L
authors.lastname: Wang
authors.affiliation: 2 Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Hui-Ju
authors.initials: HJ
authors.lastname: Hsieh
authors.affiliation: 1 Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Shen
authors.affiliation: 2 Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Powel H
authors.initials: PH
authors.lastname: Brown
authors.affiliation: 3 Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China.
authors.forename: Kaixiong
authors.initials: K
authors.lastname: Tao
authors.affiliation: 2 Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|4 Department of Clinical Oncology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Ivan P
authors.initials: IP
authors.lastname: Uray
authors.affiliation: 2 Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Guang
authors.initials: G
authors.lastname: Peng
keywords: ARID1A; FUCCI; cell cycle modulator; high-throughput drug screening