Microarray‐based survey of CpG islands identifies concurrent hyper‐ and hypomethylation patterns in tissues derived from patients with breast cancer

Piotrowski, Arkadiusz; Benetkiewicz, Magdalena; Menzel, Uwe; Ståhl, Teresita Díaz de; Mantripragada, Kiran Kumar; Grigelionis, Gintautas; Buckley, Patrick G.; Jankowski, Michał; Hoffman, Jacek; Bała, Dariusz; Śrutek, Ewa; Laskowski, Ryszard; Zegarski, Wojciech; Dumanski, Jan P.

doi:10.1002/gcc.20331

Cited by 40 publications

(22 citation statements)

References 41 publications

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“…Tissue-specific methylation has been reported for MT1A and MT1J; while both genes showed methylation in breast tumors, only the latter gene showed methylation in normal breast tissue [48]. This differential methylation is surprising, given that the two CpG islands lie less than 2 kilobases apart [48]. It indicates that CpG islands within the MT cluster are not necessarily coordinately regulated, an observation supported by our analysis of MT1A and MT2A methylation.…”

Section: Discussionsupporting

confidence: 81%

“…The MT genes are located in the metallothionein family gene cluster, a 75-kb region of chromosome 16q [47]. Tissue-specific methylation has been reported for MT1A and MT1J; while both genes showed methylation in breast tumors, only the latter gene showed methylation in normal breast tissue [48]. This differential methylation is surprising, given that the two CpG islands lie less than 2 kilobases apart [48].…”

Section: Discussionmentioning

confidence: 99%

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DNA methylation profile of 28 potential marker loci in malignant mesothelioma

et al. 2007

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SummaryPatients with malignant mesothelioma (MM), an aggressive cancer associated with asbestos exposure, usually present clinically with advanced disease and this greatly reduces the likelihood of curative treatment. MM is difficult to diagnose without invasive techniques; the development of noninvasively detectable molecular markers would therefore be highly beneficial. DNA methylation changes in cancer cells provide powerful markers that are potentially detectable non-invasively in DNA shed into bodily fluids. Here we examined the methylation status of 28 loci in 52 MM tumors to investigate their potential as molecular markers for MM. To exclude candidate MM markers that might be positive in biopsies/pleural fluid due to contaminating surrounding non-tumor lung tissue/ DNA, we also examined the methylation of these markers in lung samples (age-or environmentallyinduced hypermethylation is frequently observed in non-cancerous lung). Statistically significantly increased methylation in MM vs. non-tumor lung samples was found for estrogen receptor 1 (ESR1; p=0.0002), solute carrier family 6 member 20 (SLC6A20; p=0.0022) and spleen tyrosine kinase (SYK; p=0.0003). Examination of associations between methylation levels of the 28 loci and clinical parameters suggest associations of the methylation status of metallothionein genes with gender, Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. histology, asbestos exposure, and lymph node involvement, and the methylation status of leucine zipper tumor suppressor 1 (LZTS1) and SLC6A20 with survival. NIH Public Access

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

DNA methylation profile of 28 potential marker loci in malignant mesothelioma

et al. 2007

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“…26 A threshold was defined for each gene and each tissue, leading to significant differences in the methylation frequencies of the genes examined, even though promoter methylation in normal, non-neoplastic tissues has been demonstrated previously. [13][14][15]17,28,29 Therefore, taking NLT for threshold calculation in real-time MSP may lead to false negative results for promoter methylation. 26,30 In our study, lower APC methylation in CT compared to HCC and NLT (97.5 in HCC vs. 6.6 in CT, both p < 0.001) could be explained by the relative lower amount of hepatocytes compared to connective tissue in cirrhosis.…”

Section: Discussionmentioning

confidence: 99%

Quantitative promoter methylation analysis of hepatocellular carcinoma, cirrhotic and normal liver

Harder

Opitz

Brabender

et al. 2008

Intl Journal of Cancer

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Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Little is known about its molecular pathogenesis and the relevance of DNA methylation for disease initiation and progression. Nevertheless, promoter methylation of some genes has been implicated as potential marker for HCC. Thirty-four HCC, 34 matching non-malignant, cirrhotic livers and 16 normal livers were analyzed for the methylation status of the genes p16 INK4a , GSTP1, MGMT, DAP-K and APC by quantitative methylation-specific PCR. DNA promoter methylation frequencies in HCC and matching non-malignant cirrhotic liver, respectively, were as follows: p16 INK4a (76% vs. 24%), GSTP1 (53% vs. 32%), MGMT (6 vs. 12%), DAP-K (68 vs. 100%) and APC (100 vs. 100%). GSTP1 and/or p16 INK4a promoter methylation was observed in 88% of the HCC samples. In normal liver tissue, the p16 INK4a , GSTP1 and MGMT promoter were not methylated. DAP-K was methylated in 31% and APC even in 100% of normal liver samples. Quantitative levels of methylated promoter DNA of all genes were significantly different in the various tissue types except for MGMT. Our results suggest that promoter methylation of tumor-associated genes is a common event in hepatocarcinogenesis. Significantly, higher levels and frequencies of promoter methylation in HCC were found for p16 INK4a and GSTP1 compared to non-malignant cirrhotic liver. This indicates that these epigenetic events may serve as a good marker for HCC. These data also demonstrate the importance of the quantification of methylated promoter DNA within a given sample and the use of normal tissue as controls. Quantitative analyses of methylated GSTP1 and p16 INK4a promoter may serve as a powerful molecular marker in detecting HCC in biopsies.

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“…For each condition, at least 20 clones were selected and sequenced. Results were analyzed and presented as previously described (41).…”

Section: Inhibition Of Er Stress-induced Atf6 Cleavage By the Serinementioning

confidence: 99%

The Mechanism of Cystic Fibrosis Transmembrane Conductance Regulator Transcriptional Repression during the Unfolded Protein Response

Bartoszewski

Rab

Twitty

et al. 2008

Journal of Biological Chemistry

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The unfolded protein response (UPR) aids cellular recovery by increasing the capacity and decreasing the protein load of the endoplasmic reticulum (ER). Although the main pathways of the UPR are known, the mechanisms of UPR-associated transcriptional repression have not been explored in mammalian cells. Previous studies indicate that endogenous cystic fibrosis transmembrane conductance regulator (CFTR) mRNA levels and protein maturation efficiency decrease when the UPR is activated. In the present study, we demonstrate that inhibition of CFTR expression under ER stress leads to reduced cAMP-activated chloride secretion in epithelial monolayers, an indication of diminished CFTR function. Moreover, ER stress and the UPR obliterate endogenous ⌬F508 CFTR mRNA expression in CFPAC-1 cells without affecting recombinant ⌬F508 CFTR mRNA levels or mRNA half-life. These results emphasize that transcriptional repression of CFTR under ER stress, in concert with decreased CFTR maturation efficiency, leads to diminished function. Using human CFTR promoter reporter constructs, we confined the ER stress-associated CFTR transcriptional repression to the minimal promoter. Chromatin immunoprecipitation assays established the binding of the UPR-activated ATF6 transcription factor to this region during ER stress, which links the repression to the UPR. Methylation-specific PCR (MSP) revealed hypermethylation of CpG sites inside and in the vicinity of the MAZ transcription factor binding region of CFTR, demonstrating methylation-dependent repression. Using pharmacological inhibitors, we show that both DNA methylation and histone deacetylation contribute to CFTR transcriptional inhibition. These studies provide novel insight into the mechanism of gene repression during the mammalian UPR.In eukaryotic cells, the endoplasmic reticulum (ER) 3 is the site of protein folding and assembly. The unfolded protein response (UPR) can result from ER stress brought on by any number of insults (1-3), including depletion of ER Ca 2ϩ stores (1), proteasome blockade (4), increase in the concentration of reactive oxygen species (5, 6), inflammation (7), overexpression of secretory proteins (2, 8), or altered glycosylation (9). In addition to increasing the capacity of the ER by enhancing the synthesis of membrane components and chaperones (10), the UPR also decreases the ER protein load by enhancing ERAD (11) and to some extent by inhibiting transcription and translation (10,12). Although the principal mechanisms of the UPR have been studied extensively, only limited information is available regarding the extent and specificity of transcriptional repression during the UPR. In yeast, the limited number of genes that are transcriptionally repressed by the UPR encode secreted or cell surface proteins (6). Importantly, neither the extent nor the mechanisms of UPRassociated transcriptional repression have been investigated in mammalian cells.The cystic fibrosis transmembrane conductance regulator (CFTR), an integral membrane glycoprotein expressed in the ap...

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Microarray‐based survey of CpG islands identifies concurrent hyper‐ and hypomethylation patterns in tissues derived from patients with breast cancer

Cited by 40 publications

References 41 publications

DNA methylation profile of 28 potential marker loci in malignant mesothelioma

DNA methylation profile of 28 potential marker loci in malignant mesothelioma

Quantitative promoter methylation analysis of hepatocellular carcinoma, cirrhotic and normal liver

The Mechanism of Cystic Fibrosis Transmembrane Conductance Regulator Transcriptional Repression during the Unfolded Protein Response

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