NAT10-mediated AXL mRNA N4-acetylcytidine modification promotes pancreatic carcinoma progression

Guanzhao Zong; Xing Wang; Xingya Guo; Qiuyan Zhao; Chuanyang Wang; Shien Shen; Wenqin Xiao; Qingqing Yang; Weiliang Jiang; Jie Shen; Rong Wan

doi:10.1016/j.yexcr.2023.113620

NAT10-mediated AXL mRNA N4-acetylcytidine modification promotes pancreatic carcinoma progression

Exp Cell Res. 2023 Jul 15;428(2):113620. doi: 10.1016/j.yexcr.2023.113620. Epub 2023 May 6.

Authors

Guanzhao Zong¹, Xing Wang², Xingya Guo³, Qiuyan Zhao⁴, Chuanyang Wang¹, Shien Shen¹, Wenqin Xiao³, Qingqing Yang³, Weiliang Jiang³, Jie Shen⁵, Rong Wan⁶

Affiliations

¹ Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² First Affiliated Hospital of Jiangxi Medical College, China.
³ Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴ Department of Gastroenterology, Henan Provincial People's Hospital, Zhengzhou University, Zhengzhou, China.
⁵ Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: shenjiemd@163.com.
⁶ Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: wanrongshsy@163.com.

PMID: 37156457
DOI: 10.1016/j.yexcr.2023.113620

Abstract

Although the patient's survival time in various cancers has significantly increased in recent decades, the overall 5-year survival rate of pancreatic ductal adenocarcinoma (PDAC) has remained virtually unchanged due to rapid progression and metastasis. While N-acetyltransferase 10 (NAT10) has been identified as a regulator of mRNA acetylation in many malignancies, its role in PDAC remains unclear. Here, we found that NAT10 mRNA and protein levels were upregulated in PDAC tissues. Increased NAT10 protein expression was significantly correlated with poor prognosis in PDAC patients. Through our experiments, we demonstrated that NAT10 acted as an oncogene to promote PDAC tumorigenesis and metastasis in vitro and in vivo. Mechanistically, NAT10 exerts its oncogenic effects by promoting mRNA stability of receptor tyrosine kinase AXL in an ac4C-dependent manner leading to increased AXL expression and further promoting PDAC cell proliferation and metastasis. Together, our findings highlight the critical of NAT10 in PDAC progression and reveal a novel epigenetic mechanism by which modified mRNA acetylation promotes PDAC metastasis.

Keywords: AXL; N4-acetylcytidine; NAT10; Pancreatic ductal adenocarcinoma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Pancreatic Ductal* / metabolism
Cell Proliferation / genetics
Humans
N-Terminal Acetyltransferases
Pancreatic Neoplasms* / pathology
RNA, Messenger / genetics

Substances

N-acetylcytidine
RNA, Messenger
NAT10 protein, human
N-Terminal Acetyltransferases