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

  • Nat Commun. 2019 Dec 2;10(1):5492. doi: 10.1038/s41467-019-13420-x.
Sunwang Xu  1 ,  Ming Zhan  1 ,  Cen Jiang  2 ,  Min He  1 ,  Linhua Yang  1 ,  Hui Shen  1 ,  Shuai Huang  1 ,  Xince Huang  1 ,  Ruirong Lin  1 ,  Yongheng Shi  3 ,  Qiang Liu  3 ,  Wei Chen  1 ,  Man Mohan  2 ,  Jian Wang  4
Affiliations
  • 1. Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 2. Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3. Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 4. Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. [email protected].
PMID: 31792210 DOI: 10.1038/s41467-019-13420-x
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.

Products