+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

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



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



Hepatology 47(4): 1191-1199



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. These data demonstrate that loss of GNMT induces aberrant methylation of DNA and histones, resulting in epigenetic modulation of critical carcinogenic pathways in mice.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 054180941

Download citation: RISBibTeXText

PMID: 18318442

DOI: 10.1002/hep.22159


Related references

A splicing variant leads to complete loss of function of betaine-homocysteine methyltransferase (BHMT) gene in hepatocellular carcinoma. International Journal of Biochemistry and Cell Biology 44(2): 385-392, 2012

Characterization of glycine-N-methyltransferase-gene expression in human hepatocellular carcinoma. International Journal Of Cancer. 75(5): 787-793, Ch 2, 1998

Higher susceptibility to aflatoxin B(1)-related hepatocellular carcinoma in glycine N-methyltransferase knockout mice. International Journal of Cancer 128(3): 511-523, 2011

Loss of 5α-reductase type 1 accelerates the development of hepatic steatosis but protects against hepatocellular carcinoma in male mice. Endocrinology 154(12): 4536-4547, 2013

Characterization of a glycine N-methyltransferase gene knockout mouse model for hepatocellular carcinoma: Implications of the gender disparity in liver cancer susceptibility. International Journal of Cancer 124(4): 816-826, 2009

A splicing variant leads to complete loss of function ofBetaine-homocysteine methyltransferaseBHMT gene in hepatocellular carcinoma. 2011

A DNA methylation signature associated with the epigenetic repression of glycine N-methyltransferase in human hepatocellular carcinoma. Journal of Molecular Medicine 91(8): 939-950, 2013

Functional characterization of glycine N-methyltransferase and its interactive protein DEPDC6/DEPTOR in hepatocellular carcinoma. Molecular Medicine 18: 286-296, 2012

Hepatocellular carcinoma caused by loss of heterozygosity in Lkb1 gene knockout mice. Cancer Research 62(16): 4549-4553, 2002

Loss of Ron receptor signaling leads to reduced obesity, diabetic phenotypes and hepatic steatosis in response to high-fat diet in mice. American Journal of Physiology. Endocrinology and Metabolism 308(7): E562-E572, 2015

Identification of 1,2,3,4,6-Penta-O-galloyl-β-d-glucopyranoside as a Glycine N-Methyltransferase Enhancer by High-Throughput Screening of Natural Products Inhibits Hepatocellular Carcinoma. International Journal of Molecular Sciences 17(5):, 2016

Combined loss of expression of O6-methylguanine-DNA methyltransferase and hMLH1 accelerates progression of hepatocellular carcinoma. Journal of Surgical Oncology 82(3): 194-200, 2003

Impairment of hepatic growth hormone and glucocorticoid receptor signaling causes steatosis and hepatocellular carcinoma in mice. Hepatology 54(4): 1398-1409, 2011

PPARalpha activation is essential for HCV core protein-induced hepatic steatosis and hepatocellular carcinoma in mice. Journal of Clinical Investigation 118(2): 683-694, 2008

Non-alcoholic fatty liver disease-associated hepatocellular carcinoma: effect of hepatic steatosis on major hepatocellular carcinoma features at MRI. British Journal of Radiology 91(1092): 20180345, 2018