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

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 and results: 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.