Glycine N-methyltransferase (GNMT) is a tumor suppressor that blocks the oncogenic PAK1-Cyclin D1 signaling pathways.

Recently a group led by Arthur Chen in Taiwan found that knocking out of
GNMT gene in mice causes HCC (hepatocellular carcinoma), a liver cancer,
and activates both PAK1 and Cyclin D1 genes. This clearly suggests that
GNMT is a tumor suppressor which normally down-regulates both PAK1 and Cyclin
D1 genes, and an interesting possibility arises that anti-PAK1 drugs such
as FK228 and Bio 30 could be potentially useful for the treatment of such
a liver cancer, too. GNMT is normally involved in DNA methylation among
others.


I. J. Cancer (2008)

Characterization of a glycine N-methyltransferase gene knockout mouse model
for hepatocellular carcinoma: Implications of the gender disparity in liver
cancer susceptibility

Yi-Jen Liao, Shih-Ping Liu, Cheng-Ming Lee, Chia-Hung Yen, Pei-Chun Chuang,
Chia-Yen Chen, Ting-Fen Tsai, Shiu-Feng Huang, Yan-Hwa Wu Lee,
Yi-Ming Arthur Chen*

http://www.ibms.sinica.edu.tw/mmp/chen_yi_ming-revised.pdf

Molecular Medicine Program, Institute of Public Health, School of Medicine,
National Yang-Ming University, Taipei, Taiwan

Abstract

Hepatocellular carcinoma (HCC) is the fifth common cancer in the world and
it mainly occurs in men. Glycine N-methyltransferase (GNMT) participates
in one-carbon metabolism and affects DNA methylation by regulating the ratio
of S-adenosylmethionine to S-adenosylhomocystine. Previously, we described
that the expression of GNMT was diminished in human HCC.

Here, we showed that 50% (3/6) male and 100% (7/7) female Gnmt-/- mice developed
HCC, and their mean ages of HCC development were around 17 months. In addition,
43% (3/7) of female Gnmt-/- mice had hemangioma. Wnt reporter assay demonstrated
that Gnmt is a negative regulator for canonical Wnt signaling pathway.

Beta-catenin, Cyclin D1 and c-Myc, genes related to Wnt pathway, were up-regulated
in the liver tissues from both 11 weeks and HCC stage of Gnmt-/- mice. Furthermore,
global DNA hypomethylation and aberrant expression of DNA methyltransferases
1 and 3b were found in the early and late stages of HCC development. Hierarchical
cluster analysis of 6,023 transcripts from microarray data found that gene
expression patterns of HCC tumors from male and female Gnmt-/- mice were
distinctively different.

Real-time PCR confirmed that Gadd45a, PAK1, MAPK3 and Dsup3 genes of MAP
kinase pathway were activated in Gnmt-/- mice, especially in the female
mice. Therefore, GNMT is a tumor suppressor gene for liver cancer, and it
is associated with gender disparity in liver cancer susceptibility.