SIRT1 Regulates N6 -Methyladenosine RNA Modification in Hepatocarcinogenesis by Inducing RANBP2-Dependent FTO SUMOylation.
Hepatology
; 72(6): 2029-2050, 2020 12.
Article
em En
| MEDLINE
| ID: mdl-32154934
ABSTRACT
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. 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. APPROACH ANDRESULTS:
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.CONCLUSIONS:
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 treat HCC.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Carcinoma Hepatocelular
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Chaperonas Moleculares
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Complexo de Proteínas Formadoras de Poros Nucleares
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Sirtuína 1
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Dioxigenase FTO Dependente de alfa-Cetoglutarato
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Neoplasias Hepáticas
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article