Genome-wide CRISPR screen identifies ELP5 as a determinant of gemcitabine sensitivity in gallbladder cancer

Sunwang Xu, Ming Zhan, Cen Jiang, Min He, Linhua Yang, Hui Shen, Shuai Huang, Xince Huang, Ruirong Lin, Yongheng Shi, Qiang Liu, Wei Chen, Man Mohan and Jian Wang ()
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Sunwang Xu: Shanghai Jiao Tong University
Ming Zhan: Shanghai Jiao Tong University
Cen Jiang: Shanghai Jiao Tong University School of Medicine
Min He: Shanghai Jiao Tong University
Linhua Yang: Shanghai Jiao Tong University
Hui Shen: Shanghai Jiao Tong University
Shuai Huang: Shanghai Jiao Tong University
Xince Huang: Shanghai Jiao Tong University
Ruirong Lin: Shanghai Jiao Tong University
Yongheng Shi: Shanghai Jiao Tong University
Qiang Liu: Shanghai Jiao Tong University
Wei Chen: Shanghai Jiao Tong University
Man Mohan: Shanghai Jiao Tong University School of Medicine
Jian Wang: Shanghai Jiao Tong University

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract Gemcitabine is the first-line treatment for locally advanced and metastatic gallbladder cancer (GBC), but poor gemcitabine response is universal. Here, we utilize a genome-wide CRISPR screen to identify that loss of ELP5 reduces the gemcitabine-induced apoptosis in GBC cells in a P53-dependent manner through the Elongator complex and other uridine 34 (U34) tRNA-modifying enzymes. Mechanistically, loss of ELP5 impairs the integrity and stability of the Elongator complex to abrogate wobble U34 tRNA modification, and directly impedes the wobble U34 modification-dependent translation of hnRNPQ mRNA, a validated P53 internal ribosomal entry site (IRES) trans-acting factor. Downregulated hnRNPQ is unable to drive P53 IRES-dependent translation, but rescuing a U34 modification-independent hnRNPQ mutant could restore P53 translation and gemcitabine sensitivity in ELP5-depleted GBC cells. GBC patients with lower ELP5, hnRNPQ, or P53 expression have poor survival outcomes after gemcitabine chemotherapy. These results indicate that the Elongator/hnRNPQ/P53 axis controls gemcitabine sensitivity in GBC cells.

Date: 2019
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DOI: 10.1038/s41467-019-13420-x

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