SIRT1 Regulates N6 -Methyladenosine RNA Modification in Hepatocarcinogenesis by Inducing RANBP2-Dependent FTO SUMOylation.

Hepatology : Official Journal of the American Association for the Study of Liver Diseases
Xiaoming LiuKe Cao

Abstract

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. N6 -methyladenosine (m6 A) is the most prominent modification, but the exact mechanisms on how SIRT1 regulates m6 A modification to induce hepatocarcinogenesis remain unclear. Here we demonstrate that SIRT1 exerts an oncogenic role by down-regulating fat mass and obesity-associated protein (FTO), which is an m6 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 m6 A downstream targets of FTO and tumor suppressor in HCC, and depletion of FTO by SIRT1 improves m6 A+ GNAO1 and down-regulates its mRNA expression. We demonstrate an important mechanism whereby SIRT1 destabilizes FTO, steering the m6 A+ of downstream molecules and subsequent mRNA expression in HCC tumorigenesis. Our findings uncover a target of SIRT1 for therapeutic agents to tre...Continue Reading

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Citations

Oct 6, 2020·Frontiers in Cell and Developmental Biology·Yang LiRuipeng Jia
May 24, 2020·Cancers·Yetirajam Rajesh, Devanand Sarkar
May 1, 2021·Journal of Experimental & Clinical Cancer Research : CR·Fenghua TanCan Guo
Apr 20, 2021·Frontiers in Cell and Developmental Biology·Enakshi SivasudhanRong Rong
Jul 12, 2021·Experimental Hematology & Oncology·Junchao HuangWendong Gu
Jun 15, 2021·Drug Discovery Today·Sabrina GarboCecilia Battistelli
Aug 27, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Xiao-Fei PengWen-Chu Ye

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