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

M. Luz Martínez-Chantar, Mercedes Vázquez-Chantada, Usue Ariz, Nuria Martínez, Marta Varela, Zigmund Luka, Antonieta Capdevila, Juan Rodríguez, Ana M. Aransay, Rune Matthiesen, Heping Yang, Diego F. Calvisi, Manel Esteller, Mario Fraga, Shelly C. Lu, Conrad Wagner, José M. Mato

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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 significandy 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.

Original languageEnglish (US)
Pages (from-to)1191-1199
Number of pages9
JournalHepatology
Volume47
Issue number4
DOIs
StatePublished - Apr 2008
Externally publishedYes

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Glycine N-Methyltransferase
Hepatocellular Carcinoma
Genes
Liver
S-Adenosylmethionine
Transducers
Histones
Janus Kinase 1
Cytokines
Janus Kinases
Neoplasms
Critical Pathways
DNA Methylation
Fatty Liver
Enzymes
Liver Neoplasms
Transaminases
Epigenomics
Knockout Mice
Liver Cirrhosis

ASJC Scopus subject areas

  • Hepatology

Cite this

Martínez-Chantar, M. L., Vázquez-Chantada, M., Ariz, U., Martínez, N., Varela, M., Luka, Z., ... Mato, J. M. (2008). Loss of the glycine N-methyltransferase gene leads to steatosis and hepatocellular carcinoma in mice. Hepatology, 47(4), 1191-1199. https://doi.org/10.1002/hep.22159

Loss of the glycine N-methyltransferase gene leads to steatosis and hepatocellular carcinoma in mice. / Martínez-Chantar, M. Luz; Vázquez-Chantada, Mercedes; Ariz, Usue; Martínez, Nuria; Varela, Marta; Luka, Zigmund; Capdevila, Antonieta; Rodríguez, Juan; Aransay, Ana M.; Matthiesen, Rune; Yang, Heping; Calvisi, Diego F.; Esteller, Manel; Fraga, Mario; Lu, Shelly C.; Wagner, Conrad; Mato, José M.

In: Hepatology, Vol. 47, No. 4, 04.2008, p. 1191-1199.

Research output: Contribution to journalArticle

Martínez-Chantar, ML, Vázquez-Chantada, M, Ariz, U, Martínez, N, Varela, M, Luka, Z, Capdevila, A, Rodríguez, J, Aransay, AM, Matthiesen, R, Yang, H, Calvisi, DF, Esteller, M, Fraga, M, Lu, SC, Wagner, C & Mato, JM 2008, 'Loss of the glycine N-methyltransferase gene leads to steatosis and hepatocellular carcinoma in mice', Hepatology, vol. 47, no. 4, pp. 1191-1199. https://doi.org/10.1002/hep.22159
Martínez-Chantar ML, Vázquez-Chantada M, Ariz U, Martínez N, Varela M, Luka Z et al. Loss of the glycine N-methyltransferase gene leads to steatosis and hepatocellular carcinoma in mice. Hepatology. 2008 Apr;47(4):1191-1199. https://doi.org/10.1002/hep.22159
Martínez-Chantar, M. Luz ; Vázquez-Chantada, Mercedes ; Ariz, Usue ; Martínez, Nuria ; Varela, Marta ; Luka, Zigmund ; Capdevila, Antonieta ; Rodríguez, Juan ; Aransay, Ana M. ; Matthiesen, Rune ; Yang, Heping ; Calvisi, Diego F. ; Esteller, Manel ; Fraga, Mario ; Lu, Shelly C. ; Wagner, Conrad ; Mato, José M. / Loss of the glycine N-methyltransferase gene leads to steatosis and hepatocellular carcinoma in mice. In: Hepatology. 2008 ; Vol. 47, No. 4. pp. 1191-1199.
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T1 - Loss of the glycine N-methyltransferase gene leads to steatosis and hepatocellular carcinoma in mice

AU - Martínez-Chantar, M. Luz

AU - Vázquez-Chantada, Mercedes

AU - Ariz, Usue

AU - Martínez, Nuria

AU - Varela, Marta

AU - Luka, Zigmund

AU - Capdevila, Antonieta

AU - Rodríguez, Juan

AU - Aransay, Ana M.

AU - Matthiesen, Rune

AU - Yang, Heping

AU - Calvisi, Diego F.

AU - Esteller, Manel

AU - Fraga, Mario

AU - Lu, Shelly C.

AU - Wagner, Conrad

AU - Mato, José M.

PY - 2008/4

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N2 - 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 significandy 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.

AB - 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 significandy 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.

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