CRISPR-Cas9 screening identifies INTS3 as an anti-apoptotic RNA-binding protein and therapeutic target for colorectal cancer

Zhiwei Wang; Cheng Zhang; Jing Guo; Yanmei Yang; Peixian Li; Ziyan Wang; Sijia Liu; Lulu Zhang; Xiaoyu Zeng; Jincheng Zhai; Xinyong Wang; Qi Zhao; Zhenzhen Chen; Pingping Zhu; Qiankun He

doi:10.1016/j.isci.2024.109676

CRISPR-Cas9 screening identifies INTS3 as an anti-apoptotic RNA-binding protein and therapeutic target for colorectal cancer

iScience. 2024 Apr 6;27(5):109676. doi: 10.1016/j.isci.2024.109676. eCollection 2024 May 17.

Authors

Affiliations

¹ School of Life Sciences, Zhengzhou University, 100 Kexue Road, Zhengzhou 450001, China.
² Research Center of Basic Medicine, Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450001, China.
³ Department of oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.

Abstract

Growing evidences indicate that RNA-binding proteins (RBPs) play critical roles in regulating the RNA splicing, polyadenylation, stability, localization, translation, and turnover. Abnormal expression of RBPs can promote tumorigenesis. Here, we performed a CRISPR screen using an RBP pooled CRISPR knockout library and identified 27 potential RBPs with role in supporting colorectal cancer (CRC) survival. We found that the deletion/depletion of INTS3 triggered apoptosis in CRC. The in vitro experiments and RNA sequencing revealed that INTS3 destabilized pro-apoptotic gene transcripts and contributed to the survival of CRC cells. INTS3 loss delayed CRC cells growth in vivo. Furthermore, delivery of DOTAP/cholesterol-mshINTS3 nanoparticles inhibited CRC tumor growth. Collectively, our work highlights the role of INTS3 in supporting CRC survival and provides several novel therapeutic targets for treatment.

Keywords: Cancer; Molecular biology.