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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 & Jian Wang, 2019. "Genome-wide CRISPR screen identifies ELP5 as a determinant of gemcitabine sensitivity in gallbladder cancer," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13420-x
    DOI: 10.1038/s41467-019-13420-x
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    Cited by:

    1. Yutian Zou & Shaoquan Zheng & Xinhua Xie & Feng Ye & Xiaoqian Hu & Zhi Tian & Shu-Mei Yan & Lu Yang & Yanan Kong & Yuhui Tang & Wenwen Tian & Jindong Xie & Xinpei Deng & Yan Zeng & Zhe-Sheng Chen & Ha, 2022. "N6-methyladenosine regulated FGFR4 attenuates ferroptotic cell death in recalcitrant HER2-positive breast cancer," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Yi-Yu Chen & Jing-Yu Ge & Si-Yuan Zhu & Zhi-Ming Shao & Ke-Da Yu, 2022. "Copy number amplification of ENSA promotes the progression of triple-negative breast cancer via cholesterol biosynthesis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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