Haplotypes, Loss of Heterozygosity, and Expression Levels of Glycine <i>N</i>-Methyltransferase in Prostate Cancer

Huang, Yu Chuen; Lee, Cheng Ming; Chen, Marcelo; Chung, Ming Yi; Chang, Yen; Huang, Wen‐Yen; Ho, Donald Ming Tak; Pan, Chin Chen; Wu, Tsung-Tien; Yang, Stone; Lin, Ming; Hsieh, Jer Tsong; Chen, Yi Ming Arthur

doi:10.1158/1078-0432.ccr-06-1551

Cited by 47 publications

(69 citation statements)

References 28 publications

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“…18 This group has reported that GNMT expression is localized in the cytoplasm of hepatocytes 19 and in both the cytoplasm and nucleus of prostate epithelium. 12 Their findings are consistent with our immunohistochemical data, indicating that GNMT expression is predominantly located in the cytoplasm and scattered in the nuclei of prostate cells.…”

Section: Discussionsupporting

confidence: 92%

“…GNMT may have an important role in promoting prostate cancer cell growth via the regulation of apoptosis. Our results seem to disagree with previous findings that GNMT is a tumor susceptibility gene, [10][11][12] but agree with the previous findings that GNMT activity is linked with the progression of cancer. 5 According to our findings, we hypothesize that GNMT expression may correlate with malignant progression and prognosis.…”

Section: Discussioncontrasting

confidence: 88%

“…Huang et al 12 have reported that immunohistochemical results show abundant GNMT expression in normal prostatic and benign prostatic hyperplasia tissues, whereas its expression is diminished in prostate cancer tissues. In our study, GNMT expression was predominantly low in normal prostatic tissues, whereas it was predominantly high in the prostate cancer tissues (Table 2).…”

Section: Discussionmentioning

confidence: 99%

“…11 A significant proportion of human prostate cancers show a loss of heterozygosity of the GNMT gene. 12 Furthermore, immunohistochemical results show abundant GNMT expression in normal tissues, whereas this expression is diminished in prostate cancer tissues 12 and cholangiocarcinoma tissues. 13 These studies suggest that GNMT is a tumor susceptibility gene for prostate cancer.…”

mentioning

confidence: 99%

“…GNMT had different roles in carcinogenesis and progression between the studies of Sreekumar et al 5 and those of others. 10,12,13 It therefore remains controversial whether the GNMT gene is tumor susceptible.…”

mentioning

confidence: 99%

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The important role of glycine N-methyltransferase in the carcinogenesis and progression of prostate cancer

et al. 2011

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Glycine N-methyltransferase (GNMT) has a role in the metabolism of methionine as well as in gluconeogenesis. It has recently been reported that the GNMT gene acts as a tumor-susceptible gene. However, little is known about the specific function of GNMT in carcinogenesis and malignant progression. To better our understanding of the function of GNMT in prostate cancer, we used siRNAs to examine the effects of GNMT knockdown on cell proliferation and the cell cycle. In addition, the relation between immunohistochemical GNMT expression and clinicopathologic parameters was investigated in 148 prostate cancer tissues. Here, we show that siRNAmediated GNMT knockdown results in an inhibition of proliferation, and induces G1 arrest and apoptosis in prostate cancer cell lines. Moreover, high cytoplasmic GNMT expression was also correlated with a higher Gleason score (Po0.001) and higher pT stage (P ¼ 0.027). The patients with high GNMT cytoplasmic expression showed significantly lower disease-free survival rates than patients with low expression (Po0.001). High GNMT cytoplasmic expression had a significant impact on patient disease-free survival in multivariate analysis (P ¼ 0.005). This is the first investigation to reveal the novel finding that GNMT may have an important role in promoting prostate cancer cell growth via the regulation of apoptosis and contribute to the progression of prostate cancer. The modulation of GNMT expression or function may be a strategy for developing novel therapeutics for prostate cancer. GNMT may represent a novel marker of malignant progression and poor prognosis in prostate cancer.

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Section: Discussionsupporting

confidence: 92%

Section: Discussioncontrasting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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The important role of glycine N-methyltransferase in the carcinogenesis and progression of prostate cancer

et al. 2011

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

Liao¹,

Liu

Lee

et al. 2008

Intl Journal of Cancer

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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 Gnmt2/2 mice developed HCC, and their mean ages of HCC development were 17 and 16.5 months, respectively. In addition, 42.9% (3/7) of female Gnmt2/2 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 upregulated in the liver tissues from both 11 weeks and HCC stage of Gnmt2/2 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 Gnmt2/2 mice were distinctively different. Real-time PCR confirmed that Gadd45a, Pak1, Mapk3 and Dsup3 genes of mitogen-activated protein kinase (MAPK) pathway were activated in Gnmt2/2 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. '

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Sarcosine and other metabolites along the choline oxidation pathway in relation to prostate cancer—A large nested case–control study within the JANUS cohort in Norway

Vogel

Ulvik

Meyer

et al. 2013

Intl Journal of Cancer

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Methyl group donors and intermediates of one-carbon metabolism affect DNA synthesis and DNA methylation, and may thereby affect prostate carcinogenesis. Choline, the precursor of betaine, and the one-carbon metabolite sarcosine have been associated with increased prostate cancer risk. Within JANUS, a prospective cohort in Norway (n 5 317,000) with baseline serum samples, we conducted a nested case-control study among 3,000 prostate cancer cases and 3,000 controls. Using conditional logistic regression, odds ratios (ORs) and 95% confidence intervals (CIs) for prostate cancer risk were estimated according to quintiles of circulating betaine, dimethylglycine (DMG), sarcosine, glycine and serine. High sarcosine and glycine concentrations were associated with reduced prostate cancer risk of borderline significance (sarcosine: highest vs. lowest quintile OR 5 0.86, CI 5 0.72-1.01, p trend 5 0.03; glycine: OR 5 0.83, CI 5 0.70-1.00, p trend 5 0.07). Serum betaine, DMG and serine were not associated with prostate cancer risk. However, individuals with a high glycine/serine ratio were at decreased prostate cancer risk (OR 5 0.74, CI 5 0.69-0.85, p trend < 0.001). This population-based study suggested that men with high serum sarcosine or glycine concentrations have modestly reduced prostate cancer risk. Ratios of metabolites reflecting one-carbon balance may be associated with prostate cancer risk, as demonstrated for the glycine/serine ratio, and should be explored in future studies.The folate-mediated one-carbon metabolism, which involves B-vitamins as enzymatic cofactors, is characterized by the transfer of methyl groups and may affect carcinogenesis by influencing methylation and synthesis of DNA.1 Betaine and its precursor choline may act as methyl group sources, 2 whereas intermediates involved in the transfer of one-carbon units may be hypothesized to reflect bioavailability of methyl groups.3 These factors may therefore affect the development and growth of cancer and should be investigated when studying the role of one-carbon metabolism in carcinogenesis. Interestingly, a high S-adenosylmethionine/S-adenosylhomocysteine ratio, which facilitates transmethylation reactions, has been associated with carcinogenesis. 4 Similarly, it may be hypothesized that ratios of one-carbon metabolites, which might reflect one-carbon balance, are related to carcinogenesis.Prostate cancer is the second most frequently diagnosed cancer among men globally. 5 Results from observational studies suggest that high concentrations of circulating folate or high vitamin B12 status are associated with increased prostate cancer risk, although reported associations were modest and sometimes inconsistent.6-8 Although increased prostate cancer risk was suggested in one trial among subjects receiving folic acid supplements, 9 recent meta-analyses did not suggest an association with increased prostate cancer risk. 10,11 Nevertheless, an observational population-based study previously showed

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Haplotypes, Loss of Heterozygosity, and Expression Levels of Glycine N-Methyltransferase in Prostate Cancer

Cited by 47 publications

References 28 publications

The important role of glycine N-methyltransferase in the carcinogenesis and progression of prostate cancer

The important role of glycine N-methyltransferase in the carcinogenesis and progression of prostate cancer

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

Sarcosine and other metabolites along the choline oxidation pathway in relation to prostate cancer—A large nested case–control study within the JANUS cohort in Norway

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