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

Mar 11, 2020Hepatology (Baltimore, Md.)

SIRT1 controls RNA modification in liver cancer by triggering RANBP2-dependent FTO protein modification

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Abstract

SIRT1 may play an oncogenic role in hepatocellular carcinoma by down-regulating fat mass and obesity-associated protein (FTO).

SIRT1 is positively correlated with malignancy and metastasis in hepatocellular carcinoma (HCC).
FTO, an mA demethylase, is destabilized by SIRT1, promoting its degradation.
The activation of RANBP2 by SIRT1 is essential for the SUMOylation of FTO at the K-216 site.
GNAO1 is identified as a downstream target of FTO and acts as a tumor suppressor in HCC.
Depletion of FTO by SIRT1 leads to improved levels of mAGNAO1 and reduced mRNA expression.

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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-methyladenosine (mA) is the most prominent modification, but the exact mechanisms on how SIRT1 regulates mA modification to induce hepatocarcinogenesis remain unclear. 6 6 6

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 mA 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 mA downstream targets of FTO and tumor suppressor in HCC, and depletion of FTO by SIRT1 improves mAGNAO1 and down-regulates its mRNA expression. 6 6 6 +

CONCLUSIONS: We demonstrate an important mechanism whereby SIRT1 destabilizes FTO, steering the mAof downstream molecules and subsequent mRNA expression in HCC tumorigenesis. Our findings uncover a target of SIRT1 for therapeutic agents to treat HCC. 6 +

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

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