Increased Cytosine DNA-Methyltransferase Activity During Colon Cancer Progression

Issa, Jean–Pierre J.; Vertino, Paula M.; Wu, Jianjun; Sazawal, Sudha; Paul, C.; Nelkin, Barry D.; Hamilton, Stanley R.; Baylin, Stephen B.

doi:10.1093/jnci/85.15.1235

Cited by 284 publications

(180 citation statements)

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“…21 Our results of elevated DNA methyltransferase levels in leukaemia are similar to studies in colon cancer that have used quantitative RT-PCR assays, where an average of 3.7-fold 23 and 2.6-fold 24 increases in DNA MTase transcripts were reported when normalised with GAPDH. Lee et al 24 also found that the level of DNA MTase expression in colon cancer was 1.8-fold higher when normalised to actin, however, no significant elevation was detected when normalised to histone H4.…”

Section: Discussionsupporting

confidence: 85%

“…DNA MTase expression has been assayed previously in lung, liver and colon tumour samples using a wide range of methods, including protein-based assays 21,22 and RNA-based assays 20,[22][23][24]37 and the results obtained have been variable. However, in this study we developed a standardised competitive RT-PCR assay which enabled accurate measurement of DNA MTase mRNA expression within and between samples.…”

Section: Discussionmentioning

confidence: 99%

“…20 DNA MTase activity has been shown to increase progressively with advancing stages of both human colon and lung cancer. 21,22 Elevated levels of DNA MTase mRNA transcripts have been reported in colon cancer when compared to normal colon mucosa. Using non-quantitative reverse transcription RT-PCR assay, a 200-fold increase in DNA MTase mRNA levels was reported comparing colon cancers to normal mucosa, 20 whereas increases of 3.7-and 2.5-fold were found in later studies using quantitative RT-PCR 23 and RNAase protection assays, 24 respectively.…”

Section: Introductionmentioning

confidence: 99%

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Increased DNA methyltransferase expression in leukaemia

et al. 1998

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Aberrant DNA methylation has been observed consistently in many human tumours, in particular in the CpG islands of tumour suppressor genes, but the underlying mechanism of these changes remains unclear. To determine whether DNA methyltransferase expression is increased in leukaemia, we developed a standarised competitive RT-PCR assay to measure the level of DNA methyltransferase transcripts. Using this assay on bone marrow RNA samples from 12 patients with acute leukaemia, we observed a 4.4-fold mean increase in the level of DNA methyltransferase mRNA compared with normal bone marrow. These results support but do not prove the hypothesis that an increase in DNA methyltransferase activity is associated with malignant haematological diseases and may constitute a key step in carcinogenesis.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Increased DNA methyltransferase expression in leukaemia

et al. 1998

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“…It involves distinctly ordered alterations in common oncogenes and tumour-suppressor genes (Hamilton, 1992). Genomic hypomethylation is a special feature of colorectal cancer occurring at an early stage of the disease (Goelz et al, 1985;Feinberg et al, 1988), although regional hypermethylation (Issa et al, 1994;Hiltunen et al, 1997) and increased activity of DNA methyltransferase (Issa et al, 1993) have also been reported with progression of the tumour.…”

Section: Discussionmentioning

confidence: 99%

Hypermethylation of the WT1 and calcitonin gene promoter regions at chromosome 11p in human colorectal cancer

Hiltunen

Koistinaho²,

Alhonen³

et al. 1997

Br J Cancer

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Summary The short arm of the chromosome 11, known to harbour a number of putative and established tumour-suppressor genes, is frequently hypermethylated in various human neoplasms. We subjected the promoter regions of two genes residing at lip, namely the tumour-suppressor gene WT1 (Wilms' tumour gene) (11p13) and the calcitonin gene (11p15.5), to methylation analysis in human sporadic colorectal cancer using genomic sequencing. Both genes showed significant hypermethylation of CpG sites within their promoter regions in adenomas and carcinomas compared with normal colonic mucosa. Although the WT1 promoter region was significantly hypermethylated, two CpG sites located in Spl motifs were unmethylated in the majority of cases (68-74% of carcinomas). The expression of WT1 gene, as revealed by in situ hybridization, showed no differences between normal colonic mucosa and malignant carcinoma. Together with earlier observations, our present results support the view that the short arm of human chromosome 11 is subjected to widespread regional hypermethylation in various human malignancies.

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“…Cell biology assays DNMT activity was determined as previously described (Issa et al, 1993), and normalized to protein levels. Anchorageindependent growth assays, including suspension culture, were performed as previously described (Zhang et al, 2003).…”

Section: Reporter Plasmidsmentioning

confidence: 99%

DNMT3A and DNMT3B mediate autocrine hGH repression of plakoglobin gene transcription and consequent phenotypic conversion of mammary carcinoma cells

et al. 2007

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Directed by microarray analyses, we report that autocrine human growth hormone (hGH) increased the mRNA and protein expression of DNA methyltransferase 1 (DNMT1), DNMT3A and DNMT3B in mammary carcinoma cells. Autocrine hGH stimulation of DNMT3A and DNMT3B expression was mediated by JAK2 and Src kinases, and treatment of mammary carcinoma cells with the DNMT inhibitor, 5 0 -aza-2 0 -deoxycytidine (AZA), abrogated autocrine hGH-stimulated cellular proliferation, apoptosis and anchorage-independent growth. AZA reversed the epitheliomesenchymal transition of mammary carcinoma cells induced by autocrine hGH, to an epithelioid morphology and abrogated cell migration stimulated by autocrine hGH. Autocrine hGH-stimulated hypermethylation of the first exon of the PLAKOGLOBIN gene and AZA abrogated the ability of autocrine hGH to repress plakoglobin gene transcription. Small interfering RNA (siRNA)-mediated depletion of the individual DNMT molecules did not release autocrine hGH repression of PLAKOGLOBIN promoter activity nor did individual DNMT depletion affect autocrine hGH-stimulated migration. However, concomitant siRNA-mediated depletion of both DNMT3A and DNMT3B abrogated hypermethylation of the PLAKO-GLOBIN gene stimulated by autocrine hGH and subsequent repression of plakoglobin gene transcription and increased cell migration. Thus, the autocrine hGHstimulated increases in DNMT3A and DNMT3B expression mediate repression of plakoglobin gene transcription by direct hypermethylation of its promoter and consequent phenotypic conversion of mammary carcinoma cells. Autocrine hGH, therefore, utilizes DNA methylation as a mechanism to exert its oncogenic effects in mammary carcinoma cells.

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Increased Cytosine DNA-Methyltransferase Activity During Colon Cancer Progression

Abstract: Further studies are needed to determine whether this abnormal methylation capacity plays a role in establishing the abnormal DNA methylation patterns seen in human malignancies.

Cited by 284 publications

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Increased DNA methyltransferase expression in leukaemia

Increased DNA methyltransferase expression in leukaemia

Hypermethylation of the WT1 and calcitonin gene promoter regions at chromosome 11p in human colorectal cancer

DNMT3A and DNMT3B mediate autocrine hGH repression of plakoglobin gene transcription and consequent phenotypic conversion of mammary carcinoma cells

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