Abstract
The basic mechanisms underlying promoter DNA hypermethylation in cancer are still largely unknown. It has been proposed that the levels of the methyl donor group in DNA methylation reactions, S-adenosylmethionine (SAMe), might be involved. SAMe levels depend on the glycine-N-methyltransferase (GNMT), a one-carbon group methyltransferase, which catalyzes the conversion of SAMe to S-adenosylhomocysteine in hepatic cells. GNMT has been proposed to display tumor suppressor activity and to be frequently repressed in hepatocellular carcinoma (HCC). In this study, we show that GNMT shows aberrant DNA hypermethylation in some HCC cell lines and primary tumors (20 %). GNMT hypermethylation could contribute to gene repression and its restoration in cell lines displaying hypermethylation-reduced tumor growth in vitro. In agreement, human primary tumors expressing GNMT were of smaller size than tumors showing GNMT hypermethylation. Genome-wide analyses of gene promoter methylation identified 277 genes whose aberrant methylation in HCC was associated with GNMT methylation/expression. The findings in this manuscript indicate that DNA hypermethylation plays an important role in the repression of GNMT in HCC and that loss of GNMT in human HCC could promote the establishment of aberrant DNA methylation patterns at specific gene promoters.
Highlights
Hepatocellular carcinoma (HCC) is a solid tumor with one of the highest incidences worldwide [1]
We identified a region containing seven CpG sites which was unmethylated in nontumorigenic hepatic tissues but densely or moderately methylated in three of the five HCC cell lines (HuH7, Alex, and SNU354) (Fig. 1a, upper panel)
In order to establish whether the 3′ region of the transcription start site (TSS) of GNMT aberrant hypermethylation was present in vivo, we examined the content of methylated cytosines (mC) by bisulfite pyrosequencing in 35 HCCs
Summary
Hepatocellular carcinoma (HCC) is a solid tumor with one of the highest incidences worldwide [1]. The incidence of hepatic cancer varies geographically and within ethnic groups. This variation in HCC distribution may be due to differences in exposure to hepatitis viruses and environmental pathogens [2]. HCC has a poor prognosis, leading to death because of liver failure, which may be caused due to cirrhosis and/or to tumor progression. The survival rate of patients diagnosed with HCC is quite low. When detected at an early stage, HCC can be cured by surgical resection, liver transplantation, or ablation.
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