N-acetyltransferase 10 impedes EZH2/H3K27me3/GABARAP axis mediated autophagy and facilitates lung cancer tumorigenesis through enhancing SGK2 mRNA acetylation

Nan Xiao; Hongyang Liu; Ruike Zhang; Yang Li; Xiangzhuan Zhao; Huanxiang Chen; Chenxing Zhang; Ying Zhu; Hongshen Lu; Xuanzhi Wang; Hongchun Liu; Junhu Wan

doi:10.1016/j.ijbiomac.2025.139823

N-acetyltransferase 10 impedes EZH2/H3K27me3/GABARAP axis mediated autophagy and facilitates lung cancer tumorigenesis through enhancing SGK2 mRNA acetylation

Int J Biol Macromol. 2025 Jan 13:297:139823. doi: 10.1016/j.ijbiomac.2025.139823. Online ahead of print.

Authors

Affiliations

¹ Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
² Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
³ Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. Electronic address: xingyunerliu@163.com.
⁴ Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. Electronic address: wanjh@zzu.edu.cn.

PMID: 39814292
DOI: 10.1016/j.ijbiomac.2025.139823

Abstract

N4-acetylcytidine (ac4C) is a critical RNA modification implicated in cancer progression. Currently, N-acetyltransferase 10 (NAT10) is recognized as the sole "writer" protein responsible for ac4C modification. However, the study of NAT10 and ac4C modification in lung cancer remains sparse. In this study, we observed a significant upregulation of NAT10 expression in lung cancer, which is strongly correlated with poor prognostic outcomes. In vitro and in vivo experiments have demonstrated that NAT10 facilitates the proliferation, migration, and invasion of non-small cell lung cancer (NSCLC) cells while inhibiting autophagy flux. Mechanistically, NAT10 may enhance mRNA stability through ac4c modification at the 3' untranslated region (UTR) of SGK2 mRNA. Furthermore, SGK2 interacts with EZH2 and phosphorylates it at threonine 367, leading to increased protein stability of EZH2 and a reduction in its ubiquitination. Additionally, NAT10 impedes autophagy flux by preventing the fusion of autophagosomes with lysosomes and suppressing GABARAP transcription, which is regulated by EZH2-mediated H3K27me3. In summary, our study elucidates the biological significance and molecular mechanisms of the NAT10/SGK2/EZH2 axis in the pathogenesis of lung cancer, potentially providing novel prognostic markers and therapeutic targets for its treatment.

Keywords: Autophagy; EZH2; Lung cancer; NAT10; SGK2 mRNA acetylation.