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NAT10-mediated ac4C tRNA modification promotes EGFR mRNA translation and gefitinib resistance in cancer.

Published:25 July 2023 DOI: 10.1016/j.celrep.2023.112810 PMID: 37463108
Wei Wei, Shuishen Zhang, Hui Han, Xiaochen Wang, Siyi Zheng, Zhaoyu Wang, Chunlong Yang, Lu Wang, Jieyi Ma, Siyao Guo, Juan Wang, Lianlian Liu, Junho Choe, Shuibin Lin

Abstract

Aberrant RNA modifications are frequently associated with cancers, while the underlying mechanisms and clinical significance remain poorly understood. Here, we find that the ac4C RNA acetyltransferase NAT10 is significantly upregulated in esophageal cancers (ESCAs) and associated with poor ESCA prognosis. In addition, using ESCA cell lines and mouse models, we confirm the critical functions of NAT10 in promoting ESCA tumorigenesis and progression in?vitro and in?vivo. Mechanistically, NAT10 depletion reduces the abundance of ac4C-modified tRNAs and decreases the translation efficiencies of mRNAs enriched for ac4C-modified tRNA-decoded codons. We further identify EGFR as a key downstream target that facilitates NAT10's oncogenic functions. In terms of clinical significance, we demonstrate that NAT10 depletion and gefitinib treatment synergistically inhibit ESCA progression in?vitro and in?vivo. Our data indicate the mechanisms underlying ESCA progression at the layer of mRNA translation control and provide molecular insights for the development of effective cancer therapeutic strategies.

Substances (4)

Materials
Procduct Name CAS Molecular Formula Supplier Price
RNA Polymerase III Inhibitor 577784-91-9 C19H15Cl2N3O2S2 37 suppliers $29.00-$2400.00
RNA Polymerase III Inhibitor 577784-91-9 C19H15Cl2N3O2S2 37 suppliers $29.00-$2400.00
RNA Polymerase III Inhibitor 577784-91-9 C19H15Cl2N3O2S2 37 suppliers $29.00-$2400.00
RNA Polymerase III Inhibitor 577784-91-9 C19H15Cl2N3O2S2 37 suppliers $29.00-$2400.00

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