JMJD4-demethylated RIG-I prevents hepatic steatosis and carcinogenesis

Abstract

Background Hepatocarcinogenesis is driven by necroinflammation or metabolic disorders, and the underlying mechanisms remain largely elusive. We previously found that retinoic acid-inducible gene-I (RIG-I), a sensor for recognizing RNA virus in innate immune cells, is mainly expressed by parenchymal hepatocytes in the liver. However, its roles in hepatocarcinogenesis are unknown, which is intensively investigated in this study. Methods DEN-induced necroinflammation-driven hepatocarcinogenesis and STAM NASH-hepatocarcinogenesis were carried out in hepatocyte-specific RIG-I knockout mice. The post-translational modification of RIG-I was determined by mass spectrometry, and specific antibodies against methylated lysine sites and the RIG-I lysine mutant mice were constructed to identify the functions of RIG-I methylation. Results We interestingly found that DEN-induced hepatocarcinogenesis was enhanced, while NASH-induced hepatocarcinogenesis was suppressed by hepatocyte-specific RIG-I deficiency. Further, IL-6 decreased RIG-I expression in HCC progenitor cells (HcPCs), which then viciously promoted IL-6 effector signaling and drove HcPCs to fully established HCC. RIG-I expression was increased by HFD, which then enhanced cholesterol synthesis and steatosis, and the in-turn NASH and NASH-induced hepatocarcinogenesis. Mechanistically, RIG-I was constitutively mono-methylated at K18 and K146, and demethylase JMJD4-mediated RIG-I demethylation suppressed IL-6-STAT3 signaling. The constitutive methylated RIG-I associated with AMPKα to inhibit HMGCR phosphorylation, thus promoting HMGCR enzymatic activity and cholesterol synthesis. Clinically, RIG-I was decreased in human hepatic precancerous dysplastic nodules while increased in NAFLD livers, which were in accordance with the data in mouse models. Conclusions Decreased RIG-I in HcPCs promotes necroinflammation-induced hepatocarcinogenesis, while increased constitutive methylated RIG-I enhances steatosis and NASH-induced hepatocarcinogenesis. JMJD4-demethylated RIG-I prevents both necroinflammation and NASH-induced hepatocarcinogenesis, which provides mechanistic insight and potential target for preventing HCC.

Interferon-α stimulates DExH-box helicase 58 to prevent hepatocyte ferroptosis

“…As described previously, mouse livers were digested to obtain single-cell suspensions A [ 20 ]. Dissociated single cells were stained with AO/PI for viability assessment using a Countstar Fluorescence Cell Analyzer.…”

“…DHX58 is regarded as a non-canonical RNA-binding protein (RBP) due to its ability to associate with RNAs [ 19 ]. We previously focused on the roles of DDX/DHX family members, including DDX58 and DDX46, in regulating liver physiopathology and inflammation [ 20 – 22 ]. However, the potential roles of DDX/DHX family members in the development of hepatic ferroptosis remain unknown up to now.…”

Glutamine metabolism, a double agent combating or fuelling hepatocellular carcinoma

“…A recent study showed that JMJD4 demethylates retinoic acid-inducible gene-I to prevent necroinflammation and NASH (non-alcoholic steatohepatitis)-induced hepatocarcinogenesis. 66 In this context, it is relevant to note that abnormal αKG anabolism can generate oncometabolites: isocitrate dehydrogenase 1 and 2 (IDH1/2) are enzymes that normally catalyse the interconversion of isocitrate and αKG. IDH1/2 are frequently mutated in cancers, but not in HCC, and the gain-of-function IDH1/2-mutantenzymes lead to the accumulation of the oncometabolite D-2-hydroxyglutarate, resulting in aberrant DNA and histone methylation by competitively inhibiting enzymes such as TET and JMJD.…”

Eriodictyol regulated ferroptosis, mitochondrial dysfunction, and cell viability via Nrf2/HO‐1/NQO1 signaling pathway in ovarian cancer cells

“…Habtemariam et al also revealed that eriodictyol showed neuroprotective effects and alleviated oxidative stress via activating nuclear factor erythroid 2‐related factor 2 (Nrf2)/heme oxygenase‐1 (HO‐1) axis. [ 15 ] Interestingly, Nrf2/HO‐1/NQO1 signaling pathway is also found to be involved in the development of different cancers, such as thyroid cancer, [ 16 ] prostate cancer, [ 17 ] cervical cancer, [ 18 ] and so on. Besides, the inhibiting effect of eriodictyol on tumor was also reported.…”