N6-甲基腺苷
化学
泛素连接酶
核糖核酸
癌症研究
小干扰RNA
细胞生物学
信使核糖核酸
相扑蛋白
基因沉默
生物
生物化学
泛素
基因
甲基化
甲基转移酶
作者
Xiaoming Liu,Jianye Liu,Wen Xiao,Qinghai Zeng,Hao Bo,Yuxing Zhu,Lian Gong,Dong He,Xiaowei Xing,Ruhong Li,Ming Zhou,Wei Xiong,Yanhong Zhou,Jianda Zhou,Xiaohui Li,Yijie Ding,Canxia Xu,Xiong Chen,Xiaoyan Wang,Fen Wang,Qiang Wang,Ke Cao
出处
期刊:Hepatology
[Wiley]
日期:2020-10-22
卷期号:72 (6): 2029-2050
被引量:107
摘要
Background and Aims Hepatocellular carcinoma (HCC) is associated with high malignancy rates. Recently, a known deacetylase silent information regulator 1 (SIRT1) was discovered in HCC, and its presence is positively correlated with malignancy and metastasis. N 6 ‐methyladenosine (m 6 A) is the most prominent modification, but the exact mechanisms on how SIRT1 regulates m 6 A modification to induce hepatocarcinogenesis remain unclear. Approach and Results Here we demonstrate that SIRT1 exerts an oncogenic role by down‐regulating fat mass and obesity‐associated protein (FTO), which is an m 6 A demethylase. A crucial component of small ubiquitin‐related modifiers (SUMOs) E3 ligase, RANBP2, is activated by SIRT1, and it is indispensable for FTO SUMOylation at Lysine (K)‐216 site that promotes FTO degradation. Moreover, Guanine nucleotide‐binding protein G (o) subunit alpha (GNAO1) is identified as m 6 A downstream targets of FTO and tumor suppressor in HCC, and depletion of FTO by SIRT1 improves m 6 A + GNAO1 and down‐regulates its mRNA expression. Conclusions We demonstrate an important mechanism whereby SIRT1 destabilizes FTO, steering the m 6 A + of downstream molecules and subsequent mRNA expression in HCC tumorigenesis. Our findings uncover a target of SIRT1 for therapeutic agents to treat HCC.
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