2. Academic Validation
  3. NAT10 Increases Lysosomal Acidification to Promote Esophageal Cancer Metastasis via ac4C Acetylation of ATP6V0E1 mRNA

NAT10 Increases Lysosomal Acidification to Promote Esophageal Cancer Metastasis via ac4C Acetylation of ATP6V0E1 mRNA

  • Adv Sci (Weinh). 2025 Aug;12(31):e02931. doi: 10.1002/advs.202502931.
Yu-Juan Zhan 1,  Chun-Miao Deng 1,  Lin Tang 2,  Shu-Jun Li 2,  Tao-Yang Xu 1,  Xian Wei 1,  Xin-Yi Zhang 1,  Can-Can Zheng 1,  Li Deng 3,  Cui Shao 3,  Zhong-Min Ouyang 4,  Alfred King-Yin Lam 5,  Rong Zhang 6,  Jun Liu 7,  Xing-Yuan Shi 8,  Zhen-Yu Pan 9,  Wei Dai 10,  Ming-Liang He 11,  Simon Law 10,  Xu Li 12,  Xiao-Bing Chen 13,  Cheng Zhou 14,  Bin Li 1,  Wen-Wen Xu 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Respiratory Disease, Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700, China.
  • 2 State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, The Affiliated Traditional Chinese Medicine Hospital, Guangzhou Medical University, Guangzhou, 511400, China.
  • 3 The Affiliated Traditional Chinese Medicine Hospital, Sleep Research Institute of Traditional Chinese Medicine, Guangzhou Medical University, Guangzhou, 510000, China.
  • 4 Department of Radiology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700, China.
  • 5 Cancer Molecular Pathology and Griffith Medical School, Griffith University, Gold Coast, Queensland, 4222, Australia.
  • 6 Department of Endoscopy, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
  • 7 State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510030, China.
  • 8 Department of Radiation Oncology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700, China.
  • 9 Department of Radiation Oncology, The Affiliated Huizhou Hospital, Guangzhou Medical University, Huizhou, 516000, China.
  • 10 Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, 999077, China.
  • 11 Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, 518057, China.
  • 12 Department of Thoracic Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, 350000, China.
  • 13 Department of Oncology, Henan Engineering Research Center of Precision Therapy of Gastrointestinal Cancer & Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450000, China.
  • 14 Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
PMID: 40729677 DOI: 10.1002/advs.202502931
Abstract

N-acetyltransferase 10 (NAT10)-catalyzed N4-acetylcytidine (ac4C) modification has been reported to drive tumor metastasis. Lysosomal dysregulation plays an important role in human diseases, but its function in esophageal Cancer metastasis is unclear. It remains unknown whether NAT10 regulates lysosomal function, and the underlying mechanism and treatment strategy warrants investigation. Here, a novel role of NAT10 in inducing lysosomal acidification is revealed, and the clinical and biological significance of ATP6V0E1 in tumor metastasis is uncovered. Mechanistically, NAT10 promotes the translation efficiency of ATPase H+ transporting V0 subunit e1 (ATP6V0E1) mRNA in an ac4C-dependent manner to facilitate ATP6V0E1 expression and vacuolar H+-ATPase (v-ATPase) activity, enhancing the lysosomal degradation of E-cadherin, ultimately accelerating tumor metastasis. Furthermore, G-749 is screened and identified as a novel NAT10 inhibitor capable of effectively impeding lysosomal acidification and tumor metastasis by disrupting the NAT10-Ubiquitin-specific Peptidase 39 (USP39) interaction. Overall, the results unveil a novel role of ac4C modifications in regulating lysosomal acidification and propose a potential strategy by targeting NAT10 to inhibit esophageal Cancer metastasis.

Keywords

NAT10; ac4C modification; esophageal cancer metastasis; lysosomal acidification; targeted therapy.

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