Volume 33, No 5, May 2023

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 33 Issue 5, May 2023: 355-371

ORIGINAL ARTICLES

Lysine 2-hydroxyisobutyrylation of NAT10 promotes cancer metastasis in an ac4C-dependent manner

Long Liao^1,2,† , Yan He^1,2,† , Shu-Jun Li^1,2,† , Xiao-Mei Yu^1,2,† , Zhi-Chao Liu^3,† , Yi-Yao Liang⁴ , Han Yang⁵ , Jing Yang^1,2 , Guo-Geng Zhang^1,2 , Chun-Miao Deng¹ , Xian Wei¹ , Yi-Dong Zhu^1,2 , Tao-Yang Xu^1,2 , Can-Can Zheng¹ , Chao Cheng⁶ , Ang Li⁴ , Zhi-Gang Li³ , Jin-Bao Liu⁷ , Bin Li^1,*

¹Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, State Key Laboratory of Respiratory Disease, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, Chin
²MOE Key Laboratory of Tumor Molecular Biology, National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong, China
³Department of Thoracic Surgery, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
⁴Key Laboratory of CNS Regeneration, Ministry of Education, Guangdong Key Laboratory of Non-Human Primate Research, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, Guangdong, China
⁵Department of Thoracic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
⁶Department of Thoracic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
⁷Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, and School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China
^†These authors contributed equally: Long Liao, Yan He, Shu-Jun Li, Xiao-Mei Yu, Zhi-Chao Liu
Correspondence: Bin Li(lib2128@163.com)

Posttranslational modifications add tremendous complexity to proteomes; however, gaps remain in knowledge regarding the function and regulatory mechanism of newly discovered lysine acylation modifications. Here, we compared a panel of non-histone lysine acylation patterns in metastasis models and clinical samples, and focused on 2-hydroxyisobutyrylation (Khib) due to its significant upregulation in cancer metastases. By the integration of systemic Khib proteome profiling in 20 paired primary esophageal tumor and metastatic tumor tissues with CRISPR/Cas9 functional screening, we identified N-acetyltransferase 10 (NAT10) as a substrate for Khib modification. We further showed that Khib modification at lysine 823 in NAT10 functionally contribute to metastasis. Mechanistically, NAT10 Khib modification enhances its interaction with deubiquitinase USP39, resulting in increased NAT10 protein stability. NAT10 in turn promotes metastasis by increasing NOTCH3 mRNA stability in an N4-acetylcytidine-dependent manner. Furthermore, we discovered a lead compound #7586-3507 that inhibited NAT10 Khib modification and showed efficacy in tumor models in vivo at a low concentration. Together, our findings bridge newly identified lysine acylation modifications with RNA modifications, thus providing novel insights into epigenetic regulation in human cancer. We propose that pharmacological inhibition of NAT10 K823 Khib modification constitutes a potential anti-metastasis strategy.

https://doi.org/10.1038/s41422-023-00793-4

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