Increased protein expression of DNA methyltransferase (DNMT) 1 is significantly correlated with the malignant potential and poor prognosis of human hepatocellular carcinomas

Abstract

Alteration of DNA methylation is one of the most consistent epigenetic changes in human cancers. DNA methyltransferase (DNMT) 1 is a major enzyme involved in establishing genomic methylation patterns. Most of the studies concerning DNMT1 expression in human cancers have been performed only at the mRNA level. To directly examine DNMT1 protein expression levels during human hepatocarcinogenesis, 16 histologically normal liver tissues, 51 noncancerous liver tissues exhibiting chronic hepatitis or cirrhosis, which are considered to be precancerous conditions, and 53 hepatocellular carcinomas (HCCs) were subjected to immunohistochemic examination. If more than 20% of the cells exhibited nuclear DNMT1 staining, the tissue sample was considered to be DNMT1-positive. DNMT1 immunoreactivity was observed in 23 (43%) of the HCCs, but in none (0%) of the histologically normal liver or noncancerous liver tissues exhibiting chronic hepatitis or cirrhosis. The incidence of increased DNMT1 protein expression in HCCs correlated significantly with poor tumor differentiation (p ‫؍‬ 0.0006) and portal vein involvement (p ‫؍‬ 0.0002). Moreover, the recurrence-free (p ‫؍‬ 0.0001) and overall (p < 0.0001) survival rates of patients with HCCs exhibiting increased DNMT1 protein expression were significantly lower than those of patients with HCCs that did not exhibit increased expression. Increased DNMT1 protein expression may play a critical role in the malignant progression of HCCs and be a biologic predictor of both HCC recurrence and a poor prognosis in HCC patients. © 2003 Wiley-Liss, Inc. Key words: DNA methylation, chronic hepatitis, liver cirrhosis, hepatocarcinogenesisAberrant DNA methylation is one of the most consistent epigenetic changes in human cancers. [1][2][3][4] Generally, the overall DNA methylation level is lower in cancers than in normal tissues. 5 However, some loci tend to exhibit increased DNA methylation in cancers, 6 -8 whereas others are often hypomethylated. 9 DNA methylation may play a role in carcinogenesis by virtue of 3 mechanisms: (i) DNA cytosine methylation facilitates gene mutation, as 5-methylcytosine is deaminated to thymine; 10 (ii) aberrant DNA methylation may be associated with allelic loss 9,11-13 and (iii) DNA methylation occurs frequently in CpG islands near regulatory regions of genes and affects the transcription of specific genes. [1][2][3][4] To date, 3 enzymes that possess DNA methyltransferase (DNMT) activity-DNMT1, 14 DNMT3a and DNMT3b, 15 -have been confirmed. Of these, DNMT1 is the major and best known. As DNMT1 has a preference for hemimethylated, rather than unmethylated, substrates in vitro 16 and targets replication foci by binding to proliferating cell nuclear antigen (PCNA), 17 it was recognized as the "maintenance" DNMT that copies methylation patterns after DNA replication. However, some researchers have proposed that DNMT1 possesses both maintenance and de novo DNA methylation activity in vivo, regardless of its preference for substrates in vitro. 4,18 Moreover, recent studies...

High expression of DNA methyltransferases in primary human medulloblastoma

“…Increased DNMT1 expression indicates worse outcomes in several types of cancers, such as gastric cancer, hepatocellular carcinomas and pancreatic ductal adenocarcinoma [10,26,33]. In contrast, our analysis showed no difference in disease outcome when comparing patients with no/weak and moderate/strong expression of three DNMTs, so DNMTs are not predictive markers for medulloblastoma survival.…”

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Induces Retinoic Acid Receptor β Hypermethylation through DNA Methyltransferase 1 Accumulation in Esophageal Squamous Epithelial Cells

“…DNMT1 plays an important role in the maintenance of DNA methylation status. Overexpression of DNMT1 has been detected in many cancers, such as gastric cancer (Etoh et al, 2004), hepatic cancer (Saito et al, 2003), endometrial cancer (Liao et al, 2008), prostate cancer (Morey Kinney et al, 2008) and pancreatic cancer (Peng et al, 2005), suggesting that DNMT1 overexpression has some significance during tumor carcinogenesis. Previously, our data demonstrated that the expression of DNMT1 was significantly higher both at the protein and mRNA levels in most ESCC tissues compared to paired noncancerous tissues .…”

Polymorphisms of the DNMT3B gene and risk of squamous cell carcinoma of the head and neck: A case–control study

“…Over-expression of DNMT3B has been observed in some cancer types, and it contributes to the generation of aberrant methylation in cancer [19][20][21][22][23][24][25][26]. As we previously reported, the DNMT3B contains a C-T transition polymorphism (C46359T) at a novel alternative promoter region, -149 base pairs from the transcription start site, which in in vitro assays confers a 30% increase in the promoter activity of DNMT3B [13].…”