Han Hexu, Zhang Chengcheng, Shi Wenbo, Wang Jiawei, Zhao Wenhui, Du Yanping, Zhao Zhibin, Wang Yifan, Lin Maosong, Qin Lei, Zhao Xiaoxue, Yin Qianqian, Liu Yiyi, Wang Zhongqi, Zhang Jing, You Xiaomin, Zhou Guoxiong, Wu Honghui, Ye Jun, He Xianzhong, Tian Weizhong, Yu Hong, Yuan Yin, Wang Qiang
Department of Gastroenterology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, Jiangsu, 225300, P. R. China.
Department of Medical Oncology, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 725 Wanpingnan Road, Shanghai, 200032, P. R. China.
Adv Sci (Weinh). 2025 Jan;12(2):e2404083. doi: 10.1002/advs.202404083. Epub 2024 Nov 12.
Hepatocellular carcinoma (HCC) is characterized by frequent intrahepatic and distant metastases, resulting in a poor prognosis for patients. Epithelial-mesenchymal transition (EMT) plays a pivotal role in this process. However, the expression of NOP2/Sun RNA methyltransferase 5 (NSUN5) in HCC and its role in mediating EMT remain poorly understood. In this study, clinicopathological analyses are conducted across multiple independent HCC cohorts and induced tumor formation in Nsun5-knockout mice. The findings reveal an upregulation of NSUN5 expression in tumor tissues; conversely, the absence of Nsun5 hinders the malignant progression of HCC, indicating that NSUN5 may serve as a significant oncogene in HCC. Furthermore, elevated levels of NSUN5 enhance EMT processes within HCC cells. NSUN5-knockout cells exhibit reduced invasion and migration capabilities under both in vivo and in vitro conditions, while overexpression of NSUN5 yields opposing effects. Mechanistically, high levels of NSUN5 promote the enrichment of trimethylated histone H3 at lysine 4 (H3K4me3) at the promoter region of SMAD3 through recruitment of the WDR5, thereby facilitating HCC metastasis via SMAD3-mediated EMT pathways. Collectively, this study identifies NSUN5 as a novel driver of metastasis in HCC and provides a theoretical foundation for potential therapeutic strategies against this malignancy.
肝细胞癌（HCC）的特征是频繁发生肝内和远处转移，导致患者预后不良。上皮-间质转化（EMT）在此过程中起关键作用。然而，NOP2/Sun RNA甲基转移酶5（NSUN5）在HCC中的表达及其在介导EMT中的作用仍知之甚少。在本研究中，对多个独立的HCC队列进行了临床病理分析，并在Nsun5基因敲除小鼠中诱导肿瘤形成。研究结果显示肿瘤组织中NSUN5表达上调；相反，Nsun5的缺失会阻碍HCC的恶性进展，这表明NSUN5可能是HCC中的一个重要癌基因。此外，NSUN5水平的升高会增强HCC细胞内的EMT过程。NSUN5基因敲除细胞在体内和体外条件下均表现出侵袭和迁移能力降低，而NSUN5的过表达则产生相反的效果。机制上，高水平的NSUN5通过招募WDR5促进SMAD3启动子区域赖氨酸4处三甲基化组蛋白H3（H3K4me3）的富集，从而通过SMAD3介导的EMT途径促进HCC转移。总体而言，本研究确定NSUN5是HCC转移的一个新驱动因素，并为针对这种恶性肿瘤的潜在治疗策略提供了理论基础。
