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

• DOI: 10.1016/j.celrep.2023.112810
• Publication Date: 2023-07-18T04:10:24Z
• Authors: 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
• Keywords: QH301-705.5; Gefitinib; 3. Good health; N-Terminal Acetyltransferases; ErbB Receptors; Mice; RNA, Transfer; Drug Resistance, Neoplasm; Neoplasms; Protein Biosynthesis; Cell Line, Tumor; Animals; Humans; Biology (General); CP: Cancer

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