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Aims: To explore the methylation status, function, and underlying mechanism of the imprinted gene Neuronatin (NNAT) in hepatocellular carcinoma (HCC) progression., Main Methods: Immunohistochemistry (IHC) was performed to evaluate the expression of NNAT in HCC samples. Bisulfite genomic sequencing PCR (BSP) was applied to examine the methylation status of the NNAT promoter. In addition, colony formation, 5-Ethynyl-20-deoxyuridine (EdU) assays and subcutaneous xenograft nude models were used to explore the roles of NNAT in HCC cell proliferation. Furthermore, RNA-seq and phospho-specific protein microarray assays were conducted to illustrate the underlying mechanism by which NNAT regulates HCC progression., Key Findings: NNAT was obviously downregulated in HCC tissues, and its expression level was closely associated with tumor growth and patient prognosis. The downregulation of NNAT in HCC was induced by hypermethylation of CpG islands in the promoter region, and hypermethylation was correlated with overall survival of HCC. Moreover, the enforced expression of NNAT significantly inhibited HCC cell proliferation in vitro and in vivo. Transcriptome analysis showed that the alteration of NNAT expression was mainly related to dysregulation of the PI3K-Akt signaling pathway. Finally, phospho-specific antibody microarray detection further revealed that overexpressed NNAT can increase the phosphorylation levels of LKB1, Met, and elF4E and decrease the phosphorylation levels of PTEN, which are all involved in the PI3K-Akt signaling pathway., Significance: Our research provides new insights into the epigenetic regulation of imprinted genes in tumorigenesis and implies that the imprinted gene NNAT may act as a prognostic biomarker and tumor suppressor in HCC., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022. Published by Elsevier Inc.)

Fatty liver disease is a spectrum of liver pathologies ranging from simple hepatic steatosis to non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and culminating with the development of cirrhosis or hepatocellular carcinoma (HCC). The pathogenesis of NAFLD is complex and diverse, and there is a lack of effective treatment measures. In this review, we address hepatokines identified in the pathogenesis of NAFLD and NASH, including the signaling of FXR/RXR, PPARα/RXRα, adipogenesis, hepatic stellate cell activation/liver fibrosis, AMPK/NF-κB, and type 2 diabetes. We also highlight the interaction between hepatokines, and cytokines or peptides secreted from muscle (myokines), adipose tissue (adipokines), and hepatic stellate cells (stellakines) in response to certain nutritional and physical activity. Cytokines exert autocrine, paracrine, or endocrine effects on the pathogenesis of NAFLD and NASH. Characterizing signaling pathways and crosstalk amongst muscle, adipose tissue, hepatic stellate cells and other liver cells will enhance our understanding of interorgan communication and potentially serve to accelerate the development of treatments for NAFLD and NASH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yang, Lu, Zhou, Fan, Barbier-Torres, Steggerda, Yang and Yang.)

Methionine adenosyltransferase 1A (MAT1A) is a tumor suppressor downregulated in hepatocellular carcinoma and cholangiocarcinoma, two of the fastest rising cancers worldwide. We compared MATα1 (protein encoded by MAT1A) interactome in normal versus cancerous livers by mass spectrometry to reveal interactions with 14-3-3ζ. The MATα1/14-3-3ζ complex was critical for the expression of 14-3-3ζ. Similarly, the knockdown and small molecule inhibitor for 14-3-3ζ (BV02), and ChIP analysis demonstrated the role of 14-3-3ζ in suppressing MAT1A expression. Interaction between MATα1 and 14-3-3ζ occurs directly and is enhanced by AKT2 phosphorylation of MATα1. Blocking their interaction enabled nuclear MATα1 translocation and inhibited tumorigenesis. In contrast, overexpressing 14-3-3ζ lowered nuclear MATα1 levels and promoted tumor progression. However, tumor-promoting effects of 14-3-3ζ were eliminated when liver cancer cells expressed mutant MATα1 unable to interact with 14-3-3ζ. Taken together, the reciprocal negative regulation that MATα1 and 14-3-3ζ exert is a key mechanism in liver tumorigenesis., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background and Aims: Forkhead box M1 (FOXM1) and nuclear factor kappa B (NF-ĸB) are oncogenic drivers in liver cancer that positively regulate each other. We showed that methionine adenosyltransferase 1A (MAT1A) is a tumor suppressor in the liver and inhibits NF-ĸB activity. Here, we examined the interplay between FOXM1/NF-κB and MAT1A in liver cancer., Approach and Results: We examined gene and protein expression, effects on promoter activities and binding of proteins to promoter regions, as well as effects of FOXM1 inhibitors T0901317 (T0) and forkhead domain inhibitory-6 (FDI-6) in vitro and in xenograft and syngeneic models of liver cancer. We found, in both hepatocellular carcinoma and cholangiocarcinoma, that an induction in FOXM1 and NF-κB expression is accompanied by a fall in MATα1 (protein encoded by MAT1A). The Cancer Genome Atlas data set confirmed the inverse correlation between FOXM1 and MAT1A. Interestingly, FOXM1 directly interacts with MATα1 and they negatively regulate each other. In contrast, FOXM1 positively regulates p50 and p65 expression through MATα1, given that the effect is lost in its absence. FOXM1, MATα1, and NF-κB all bind to the FOX binding sites in the FOXM1 and MAT1A promoters. However, binding of FOXM1 and NF-κB repressed MAT1A promoter activity, but activated the FOXM1 promoter. In contrast, binding of MATα1 repressed the FOXM1 promoter. MATα1 also binds and represses the NF-κB element in the presence of p65 or p50. Inhibiting FOXM1 with either T0 or FDI-6 inhibited liver cancer cell growth in vitro and in vivo. However, inhibiting FOXM1 had minimal effects in liver cancer cells that do not express MAT1A., Conclusions: We have found a crosstalk between FOXM1/NF-κB and MAT1A. Up-regulation in FOXM1 lowers MAT1A, but raises NF-κB, expression, and this is a feed-forward loop that enhances tumorigenesis., (© 2020 by the American Association for the Study of Liver Diseases.)