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
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DOI：
10.1002/hep.22159
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发表时间：
2008-04-01
期刊：
影响因子：
13.5
通讯作者：
Mato, Jose M.
中科院分区：
文献类型：
--
作者：
Martinez-Chantar, M. Luz;Vazquez-Chantada, Mercedes;Mato, Jose M.
甘氨酸n -甲基转移酶（Glycine N-methyltransferase， GNMT）是肝脏过量s -腺苷甲硫氨酸（SAMe）分解代谢的主要酶。GNMT在肝细胞癌（HCC）中缺失，信使RNA （mRNA）水平在HCC风险患者的肝脏中显著降低，GNMT被认为是肝癌的肿瘤易感基因。几个患有肝脏疾病的儿童被鉴定为GNMT基因突变，这进一步表明这种酶在肝功能中起着重要作用。在目前的研究中，我们研究了gnmt敲除（GNMT-KO）小鼠的肝脏病理发展，包括HCC。GNMT-KO小鼠血清转氨酶、蛋氨酸和SAMe水平升高，并发生肝脏脂肪变性、纤维化和HCC。我们发现GNMT-KO小鼠肝肿瘤中Ras和Janus激酶(JAK)/信号换能器和转录激活因子（STAT）通路的激活增加，与Ras抑制剂Ras-关联结构域家族/肿瘤抑制因子（RASSF） 1和4以及JAK/STAT抑制剂细胞因子信号传导抑制因子（SOCS） 1-3和细胞因子诱导的sh2蛋白的抑制一致。最后，我们发现GNMT-KO小鼠HCC中RASSF1和SOCS2启动子的甲基化以及组蛋白3中三甲基化赖氨酸27与这两个基因的结合增加。结论：这些数据表明，GNMT的缺失会诱导DNA和组蛋白的异常甲基化，从而导致小鼠关键致癌途径的表观遗传调控。
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.