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.


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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antimetabolites, Antineoplastic / administration & dosage*
  • Apoptosis / drug effects
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Clustered Regularly Interspaced Short Palindromic Repeats*
  • Cohort Studies
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives*
  • Female
  • Gallbladder Neoplasms / drug therapy*
  • Gallbladder Neoplasms / genetics*
  • Gallbladder Neoplasms / metabolism
  • Gemcitabine
  • Genome-Wide Association Study
  • Heterogeneous-Nuclear Ribonucleoproteins / genetics
  • Heterogeneous-Nuclear Ribonucleoproteins / metabolism
  • Humans
  • Internal Ribosome Entry Sites
  • Male
  • Middle Aged
  • RNA Processing, Post-Transcriptional
  • RNA, Transfer / genetics
  • RNA, Transfer / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism


  • Antimetabolites, Antineoplastic
  • Carrier Proteins
  • ELP5 protein, human
  • Heterogeneous-Nuclear Ribonucleoproteins
  • Internal Ribosome Entry Sites
  • SYNCRIP protein, human
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Deoxycytidine
  • RNA, Transfer
  • Gemcitabine