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Loss of the glycine N-methyltransferase gene leads to steatosis and hepatocellular carcinoma in mice

Martínez-Chantar, M. Luz and Vázquez-Chantada, Mercedes and Ariz, Usue and Martínez, Nuria and Varela, Marta and Luka, Zigmund and Capdevila, Antonieta and Rodríguez, Juan and Aransay, Ana María and Matthiesen, Rune and Yang, Heping and Calvisi, Diego Francesco and Esteller, Manel and Fraga, Mario and Lu, Shelly C. and Wagner, Conrad and Mato, José M. (2008) Loss of the glycine N-methyltransferase gene leads to steatosis and hepatocellular carcinoma in mice. Hepatology, Vol. 47 (4), p. 1191-1199. eISSN 1527-3350. Article.

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DOI: 10.1002/hep.22159

Abstract

Glycine N-methyltransferase (GNMT) is the main enzyme responsible for catabolism of excess hepatic S-adenosylmethionine (SAMe). GNMT is absent in hepatocellular carcinoma (HCC), messenger RNA (mRNA) levels are significantly lower in livers of patients at risk of developing HCC, and GNMT has been proposed to be a tumor-susceptibility gene for liver cancer. The identification of several children with liver disease as having mutations of the GNMT gene further suggests that this enzyme plays an important role in liver function. In the current study we studied development of liver pathologies including HCC in GNMT-knockout (GNMT-KO) mice. GNMT-KO mice have elevated serum aminotransferase, methionine, and SAMe levels and develop liver steatosis, fibrosis, and HCC. We found that activation of the Ras and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways was increased in liver tumors from GNMT-KO mice coincidently with the suppression of the Ras inhibitors Ras-association domain family/tumor suppressor (RASSF) 1 and 4 and the JAK/STAT inhibitors suppressor of cytokine signaling (SOCS) 1-3 and cytokine-inducible SH2-protein. Finally, we found that methylation of RASSF1 and SOCS2 promoters and the binding of trimethylated lysine 27 in histone 3 to these 2 genes was increased in HCC from GNMT-KO mice. Conclusion: These data demonstrate that loss of GNMT induces aberrant methylation of DNA and histones, resulting in epigenetic modulation of critical carcinogenic pathways in mice.

Item Type:Article
ID Code:1289
Status:Published
Refereed:Yes
Uncontrolled Keywords:Glycine N-methyltransferase (GNMT), S-adenosylmethionine (SAMe), hepatocellular carcinoma, mouse model
Subjects:Area 06 - Scienze mediche > MED/04 Patologia generale
Divisions:001 Università di Sassari > 01 Dipartimenti > Scienze biomediche
Publisher:Wiley
eISSN:1527-3350
Copyright Holders:© 2008 by the American Association for the Study of Liver Diseases
Additional Information:Pubblicato online il 19 dicembre 2007.
Deposited On:18 Aug 2009 10:04

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