Hepatic FTO is dispensable for the regulation of metabolism but counteracts HCC development in vivo

Abstract

Objective Single-nucleotide polymorphisms in the FTO gene encoding an m 6 Am and an m 6 A demethylase are associated with obesity. Moreover, recent studies have linked a dysregulation of m 6 A modifications and its machinery, including FTO, to the development of several forms of cancers. However, the functional role of hepatic FTO in metabolism and the development and progression of hepatocellular carcinoma (HCC), a proteotypic obesity-associated cancer, remains unclear. Thus, we aimed to reveal the role of hepatic FTO in metabolism and in the initiation and progression of HCC in vivo . Methods We generated mice with hepatic FTO deficiency (FTO L−KO ). The effect of hepatic FTO on metabolism was investigated by extensive metabolic phenotyping. To determine the impact of hepatic FTO on HCC development, FTO L−KO and Ctrl mice were subjected to long-term diethylnitrosamine (DEN)-induced HCC-development and the tumor initiation phase was examined via a short-term DEN protocol. Results In long-term DEN experiments, FTO L−KO mice exhibit increased HCC burden compared to Ctrl mice. In the tumor initiation phase, Ctrl mice display a dynamic regulation of FTO upon induction of liver damage, while this response is abrogated in FTO-deficient mice. Proteomic analyses revealed that liver damage-induced increases in FTO expression reduce CUL4A protein abundance. Functionally, simultaneous knockdown of Cul4a reverses the increased hepatocyte proliferation observed upon loss of FTO. Conclusion Collectively, our study demonstrates that hepatic FTO is dispensable for the control of energy homeostasis and glucose metabolism. However, we show a protective function of FTO in liver carcinogenesis and suggest the FTO-dependent dynamic mRNA demethylation of Cul4a in the initiation of HCC development contributes to this effect.

A positive-feedback loop between HBx and ALKBH5 promotes hepatocellular carcinogenesis

“…On the other hand, there are diverse molecular subtypes of HBV-HCC, which might determine the different expression pattern for certain genes [ 24 , 27 ]. In addition, the effects of ALKBH5 on carcinogenesis might relate to the stage of tumor and the different downstream molecules as shown by other epitranscriptomics enzyme such as FTO [ 28 , 29 ].…”

The functional roles, cross-talk and clinical implications of m6A modification and circRNA in hepatocellular carcinoma

“…Additionally; FTO is indispensable for the regulation of energy homeostasis and glucose metabolism in HCC. Furthermore, FTO acted as a protector in HCC carcinogenesis, and FTO-dependent dynamic mRNA demethylation of CUL4A exerted critical functions in the initiation and development of HCC 34 .…”

The emerging roles of m6A modification in liver carcinogenesis

“…Liu et al reported that SIRT1 activate RANBP2 that mediates FTO SUMOylation and degradation, and subsequently leads to m 6 A deposition in HCC tumor suppressor guanine nucleotide-binding protein G (o) subunit alpha (GNAO1) and inhibits its mRNA expression, and consequently results in liver cancer progression 139 . Recently, a study reveals that FTO plays a protective role in HCC development 143 . Hepatocyte-specific depletion of FTO not only impacts HCC initiation phase (increased tumor numbers) but also influences HCC development (increased numbers of larger tumors) by inhibiting Cul4a translation 143 .…”

“…Recently, a study reveals that FTO plays a protective role in HCC development 143 . Hepatocyte-specific depletion of FTO not only impacts HCC initiation phase (increased tumor numbers) but also influences HCC development (increased numbers of larger tumors) by inhibiting Cul4a translation 143 . Intrahepatic cholangiocarcinoma (ICC) is the second most common form of primary liver cancer.…”