NAT10-mediated ac4C tRNA modification promotes EGFR mRNA translation and gefitinib resistance in cancer
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
Affiliations
Wei Wei
Department of Otolaryngology, Center for Translational Medicine, Precision Medicine Institute, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
Shuishen Zhang
Department of Thoracic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
Hui Han
Department of Otolaryngology, Center for Translational Medicine, Precision Medicine Institute, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
Xiaochen Wang
Department of Otolaryngology, Center for Translational Medicine, Precision Medicine Institute, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
Siyi Zheng
Department of Otolaryngology, Center for Translational Medicine, Precision Medicine Institute, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
Zhaoyu Wang
Department of Otolaryngology, Center for Translational Medicine, Precision Medicine Institute, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
Chunlong Yang
Clinical Research Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China
Lu Wang
Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China
Jieyi Ma
Department of Otolaryngology, Center for Translational Medicine, Precision Medicine Institute, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
Siyao Guo
Department of Otolaryngology, Center for Translational Medicine, Precision Medicine Institute, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
Juan Wang
Division of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
Lianlian Liu
Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
Junho Choe
Department of Life Science, College of Natural Sciences, Hanyang University, Seoul 04763, Republic of Korea; Research Institute for Natural Sciences, Hanyang University, Seoul 04763, Republic of Korea; Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul 04763, Republic of Korea; Research Institute for Convergence of Basic Sciences, Hanyang University, Seoul 04763, Republic of Korea
Shuibin Lin
Department of Otolaryngology, Center for Translational Medicine, Precision Medicine Institute, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; Corresponding author
Summary: 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.
