Zhan Yu-Juan, Deng Chun-Miao, Tang Lin, Li Shu-Jun, Xu Tao-Yang, Wei Xian, Zhang Xin-Yi, Zheng Can-Can, Deng Li, Shao Cui, Ouyang Zhong-Min, Lam Alfred King-Yin, Zhang Rong, Liu Jun, Shi Xing-Yuan, Pan Zhen-Yu, Dai Wei, He Ming-Liang, Law Simon, Li Xu, Chen Xiao-Bing, Zhou Cheng, Li Bin, Xu Wen-Wen
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.
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.
Adv Sci (Weinh). 2025 Aug;12(31):e02931. doi: 10.1002/advs.202502931. Epub 2025 Jul 29.
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.
据报道，N-乙酰转移酶10（NAT10）催化的N4-乙酰胞苷（ac4C）修饰可促进肿瘤转移。溶酶体功能失调在人类疾病中起重要作用，但其在食管癌转移中的作用尚不清楚。NAT10是否调节溶酶体功能、潜在机制及治疗策略仍有待研究。在此，我们揭示了NAT10在诱导溶酶体酸化中的新作用，并发现了ATP6V0E1在肿瘤转移中的临床和生物学意义。机制上，NAT10以ac4C依赖的方式促进ATP酶H转运V0亚基e1（ATP6V0E1）mRNA的翻译效率，以促进ATP6V0E1表达和液泡H-ATP酶（v-ATP酶）活性，增强E-钙黏蛋白的溶酶体降解，最终加速肿瘤转移。此外，筛选并鉴定出G-749作为一种新型NAT10抑制剂，它能够通过破坏NAT10-泛素特异性肽酶39（USP39）相互作用有效阻碍溶酶体酸化和肿瘤转移。总体而言，这些结果揭示了ac4C修饰在调节溶酶体酸化中的新作用，并提出了一种靶向NAT10抑制食管癌转移的潜在策略。
