Nuclear localization dictates hepatocarcinogenesis suppression by glycine N-methyltransferase

Simile, Maria M.; Cigliano, Antonio; Paliogiannis, Panagiotis; Daino, Lucia; Manetti, Roberto; Feo, Claudio F; Calvisi, Diego F.; Feo, Francesco; Pascale, Rosa M.

doi:10.1016/j.tranon.2021.101239

Cited by 6 publications

(6 citation statements)

References 46 publications

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“…The consequent lower inhibition of ERK1/2 by SAM, favors the ERK1/2 regulated epithelial/mesenchymal transition (EMT) [ 44 ]. These observations support a suppressive effect of SAM on malignant transformation through ERK1/2 inhibition by multiple mechanisms, such as genetic predisposition, including increased transcription and stability of its mRNA and protein, and inhibition of proteasomal chymotrypsin-like and caspase-like activities [ 45 ].…”

Section: The Role Of Genetic Mechanisms Regulating the Susceptibility...mentioning

confidence: 54%

“…Aflatoxin B1 metabolism and its carcinogenic activity effect is modulated by GNMT [ 44 , 57 ]. Nuclear localization of the GNMT protein was found to be higher in human HCC with better prognosis (HCCB) than in HCC with poorer prognosis (HCCP) [ 45 ]. GNMT forced expression inhibits proliferation, induces apoptosis, and suppresses GNMT CYP1A1 , PREX2 , PARP1 , and NFKB gene expression by binding to their promoters in vitro in Huh7 and HepG2 cell lines [ 45 ].…”

Section: Gnmt and The Genetic Predisposition To Hccmentioning

confidence: 99%

“…Nuclear localization of the GNMT protein was found to be higher in human HCC with better prognosis (HCCB) than in HCC with poorer prognosis (HCCP) [ 45 ]. GNMT forced expression inhibits proliferation, induces apoptosis, and suppresses GNMT CYP1A1 , PREX2 , PARP1 , and NFKB gene expression by binding to their promoters in vitro in Huh7 and HepG2 cell lines [ 45 ]. This observation indicates that GNMT protein exerts a polyhedric suppressive activity during hepatocarcinogenesis, interacting and inhibiting the expression of several cancer related genes.…”

Section: Gnmt and The Genetic Predisposition To Hccmentioning

confidence: 99%

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Genetic Predisposition to Hepatocellular Carcinoma

Pascale

Calvisi²,

Feo³

et al. 2022

Metabolites

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Liver preneoplastic and neoplastic lesions of the genetically susceptible F344 and resistant BN rats cluster, respectively, with human HCC with better (HCCB) and poorer prognosis (HCCP); therefore, they represent a valid model to study the molecular alterations determining the genetic predisposition to HCC and the response to therapy. The ubiquitin-mediated proteolysis of ERK-inhibitor DUSP1, which characterizes HCC progression, favors the unrestrained ERK activity. DUSP1 represents a valuable prognostic marker, and ERK, CKS1, or SKP2 are potential therapeutic targets for human HCC. In DN (dysplastic nodule) and HCC of F344 rats and human HCCP, DUSP1 downregulation and ERK1/2 overexpression sustain SKP2-CKS1 activity through FOXM1, the expression of which is associated with a susceptible phenotype. SAM-methyl-transferase reactions and SAM/SAH ratio are regulated by GNMT. In addition, GNMT binds to CYP1A, PARP1, and NFKB and PREX2 gene promoters. MYBL2 upregulation deregulates cell cycle and induces the progression of premalignant and malignant liver. During HCC progression, the MYBL2 transcription factor positively correlates with cells proliferation and microvessel density, while it is negatively correlated to apoptosis. Hierarchical supervised analysis, regarding 6132 genes common to human and rat liver, showed a gene expression pattern common to normal liver of both strains and BN nodules, and a second pattern is observed in F344 nodules and HCC of both strains. Comparative genetics studies showed that DNs of BN rats cluster with human HCCB, while F344 DNs and HCCs cluster with HCCP.

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Section: The Role Of Genetic Mechanisms Regulating the Susceptibility...mentioning

confidence: 54%

Section: Gnmt and The Genetic Predisposition To Hccmentioning

confidence: 99%

Section: Gnmt and The Genetic Predisposition To Hccmentioning

confidence: 99%

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Genetic Predisposition to Hepatocellular Carcinoma

Pascale

Calvisi²,

Feo³

et al. 2022

Metabolites

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“…Canonically, AhR mainly targets the cytochrome P450 family 1 enzymes, including CYP1A1 [ 21 , 22 ]. When a ligand binds AhR, it translocates to the nucleus, where it induces transcription of CYP1A1 followed by an increase in CYP1A1 enzymatic activity [ 23 , 24 ].…”

Section: Discussionmentioning

confidence: 99%

ZNF165 Is Involved in the Regulation of Immune Microenvironment and Promoting the Proliferation and Migration of Hepatocellular Carcinoma by AhR/CYP1A1

Liu

Zhou

Dong

et al. 2022

Journal of Immunology Research

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The strong tumorigenic capacity and treatment resistance made hepatocellular carcinoma (HCC) a huge threat to public health. ZNF165, the kruppel family of zinc-finger-containing transcription factors, is expressed in HCC; however, its specific role in HCC and the molecular mechanism are yet to be elucidated. In this study, we observed that ZNF165 was overexpressed in liver cancer tissues and the immune microenvironment; higher ZNF165 expression was correlated with lower overall survival in liver cancer patients. The ZNF165 knockdown in Bel7402 cells revealed the impairment of the tryptophan/kynurenine/AhR/CYP1A1 axis. Moreover, the knockdown of CYP1A1 significantly inhibited the proliferation and migration of HCC cells, and ZNF165 promoted the transcriptional activity of AhR by facilitating the nuclear translocation of CYP1A1. In conclusion, the present study argued that ZNF165 was highly expressed in liver tissues and the immune microenvironment. ZNF165 promoted the proliferation and migration of HCC cells by activating the tryptophan/kynurenine/AhR/CYP1A1 axis and promoting the expression of CYP1A1.

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“…It was shown that elevated AdoMet could lead to hypermethylation of DNA and modulation of lipid metabolism through phosphatidylcholine synthesis. Furthermore, GNMT has been shown to be reduced during hepatic injury and multiple genetic analyses of human patients have found that GNMT gene expression is repressed in both NASH and hepatocellular carcinoma patients [9][10][11][12][13]. Despite this, GNMT protein downregulation and its impact on the disease process are still not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Dysregulation of S-adenosylmethionine Metabolism in Nonalcoholic Steatohepatitis Leads to Polyamine Flux and Oxidative Stress

Quinn

Rico

Merali

et al. 2022

IJMS

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Nonalcoholic fatty liver disease (NAFLD) is the number one cause of chronic liver disease worldwide, with 25% of these patients developing nonalcoholic steatohepatitis (NASH). NASH significantly increases the risk of cirrhosis and decompensated liver failure. Past studies in rodent models have shown that glycine-N-methyltransferase (GNMT) knockout results in rapid steatosis, fibrosis, and hepatocellular carcinoma progression. However, the attenuation of GNMT in subjects with NASH and the molecular basis for its impact on the disease process is still unclear. To address this knowledge gap, we show the reduction of GNMT protein levels in the liver of NASH subjects compared to healthy controls. To gain insight into the impact of decreased GNMT in the disease process, we performed global label-free proteome studies on the livers from a murine modified amylin diet-based model of NASH. Histological and molecular characterization of the animal model demonstrate a high resemblance to human disease. We found that a reduction of GNMT leads to a significant increase in S-adenosylmethionine (AdoMet), an essential metabolite for transmethylation reactions and a substrate for polyamine synthesis. Further targeted proteomic and metabolomic studies demonstrated a decrease in GNMT transmethylation, increased flux through the polyamine pathway, and increased oxidative stress production contributing to NASH pathogenesis.

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Nuclear localization dictates hepatocarcinogenesis suppression by glycine N-methyltransferase

Abstract: Highlights GNMT gene expression contributes to determine hepatocellular carcinoma (HCC) prognosis. GNMT expression is genetically determined. Nuclear GNMT binds to CYP1A1, PREX2, PARP1, and NFKB gene promoters and strongly inhibits their expression.

Cited by 6 publications

References 46 publications

Genetic Predisposition to Hepatocellular Carcinoma

Genetic Predisposition to Hepatocellular Carcinoma

ZNF165 Is Involved in the Regulation of Immune Microenvironment and Promoting the Proliferation and Migration of Hepatocellular Carcinoma by AhR/CYP1A1

Dysregulation of S-adenosylmethionine Metabolism in Nonalcoholic Steatohepatitis Leads to Polyamine Flux and Oxidative Stress

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