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

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.

journal_name

Nat Commun

journal_title

Nature communications

authors

Xu S,Zhan M,Jiang C,He M,Yang L,Shen H,Huang S,Huang X,Lin R,Shi Y,Liu Q,Chen W,Mohan M,Wang J

doi

10.1038/s41467-019-13420-x

subject

Has Abstract

pub_date

2019-12-02 00:00:00

pages

5492

issue

1

issn

2041-1723

pii

10.1038/s41467-019-13420-x

journal_volume

10

pub_type

临床试验,杂志文章

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