USP48 Is Upregulated by Mettl14 to Attenuate Hepatocellular Carcinoma via Regulating SIRT6 Stabilization
USP48 Is Upregulated by Mettl14 to Attenuate Hepatocellular Carcinoma via Regulating SIRT6 Stabilization
复制标题
Mettl14 上调 USP48，通过调节 SIRT6 稳定性来减轻肝细胞癌
DOI：
10.1158/0008-5472.can-20-4163
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发表时间：
2021-07-15
期刊：
影响因子：
11.2
通讯作者：
Tang, Bo
中科院分区：
文献类型：
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作者：
Du, Lutao;Li, Yang;Tang, Bo
利用肿瘤代谢为肝细胞癌患者的临床造福是一个正在积极研究的课题。泛素特异性多肽酶48(USP48)是泛素特异性蛋白水解酶家族中的一员，参与肿瘤生长、炎症和基因组稳定。然而，USP48在肝细胞癌发生中的作用仍不清楚。在这项研究中，我们报告了USP48在二乙基亚硝胺诱导的小鼠肝肿瘤形成过程中的表达下调，以及在人类肝癌中的表达。USP48通过在SIRT6的K33和K128位点与K48相连的去泛素化来物理结合和稳定SIRT6，这阻碍了代谢重编程来阻碍肝癌的发生。此外，甲基转移酶样14(Mettl14)诱导的M6A修饰通过维持USP48的mRNA稳定性参与了对USP48的调控。我们的工作揭示了Mettl14-USP48-SIRT6轴通过调节糖酵解而发挥的肿瘤抑制功能，为了解代谢活动在肝癌中的关键作用提供了新的见解，并为未来的治疗研究确定了一个有吸引力的靶点。这些发现表明，USP48受Mettl14诱导的M6A修饰的调节，并稳定SIRT6，以减轻肝癌的糖酵解和恶性程度。
Exploiting cancer metabolism for the clinical benefit of patients with hepatocellular carcinoma (HCC) is a topic under active investigation. Ubiquitin-specific peptidase 48 (USP48), a member of the ubiquitin-specific protease family, is involved in tumor growth, inflammation, and genome stability. However, the role of USP48 in HCC tumorigenesis remains unknown. In this study, we report that expression of USP48 is downregulated in diethylnitrosamine-induced liver tumorigenesis in mice as well as in human HCC. USP48 physically bound and stabilized SIRT6 by K48-linked deubiquitination at the K33 and K128 sites of SIRT6, which impeded metabolic reprogramming to hamper HCC tumorigenesis. Moreover, methyltransferase-like 14 (Mettl14)–induced m6A modification participated in the regulation of USP48 in HCC by maintaining USP48 mRNA stability. Our work uncovers the tumor-suppressive function of the Mettl14–USP48–SIRT6 axis via modulation of glycolysis, providing new insights into the critical roles of metabolic activities in HCC and identifying an attractive target for future treatment studies.SignificanceThese findings demonstrate that USP48 is regulated by Mettl14-induced m6A modification and stabilizes SIRT6 to attenuate HCC glycolysis and malignancy.