The endothelin receptor B (EDNRB) promoter displays heterogeneous, site specific methylation patterns in normal and tumor cells

Pao, Martha M.

doi:10.1093/hmg/10.9.903

Cited by 90 publications

(75 citation statements)

References 36 publications

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“…1C). EDNRB has been well studied by our laboratory (20). Our results indicated good correlations between methylation and lack of expression of DAPK and RASSF1A, but not for BCL2, TERT, and TNFRSF25.…”

Section: Evaluation Of Methylation and Expression In Humanmentioning

confidence: 54%

“…Apoptotic pathways are targets for epigenetic silencing (11), and several apoptosis-linked genes [RASSF1A (12), CDH1 (13)(14)(15), TMS-1 (16), APAF-1 (17), p14(ARF) (18), BCL2 (19), and EDNRB (20)] that are regulated directly or indirectly by methylation have been described. It also has been reported that methylation of DAPK is associated with bladder cancer recurrence (9).…”

Section: Introductionmentioning

confidence: 99%

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Detection of Methylated Apoptosis-Associated Genes in Urine Sediments of Bladder Cancer Patients

Friedrich

Weisenberger²,

Cheng³

et al. 2004

Clinical Cancer Research

204

178

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Purpose: There is increasing evidence for a fundamental role for epigenetic silencing of apoptotic pathways in cancer. Changes in DNA methylation can be detected with a high degree of sensitivity, so we used the MethyLight assay to determine how methylation patterns of apoptosis-associated genes change during bladder carcinogenesis and whether DNA methylation could be detected in urine sediments.Experimental Design: We analyzed the methylation status of the 5 regions of 12 apoptosis-associated genes (ARF, FADD, TNFRSF21, BAX, LITAF, DAPK, TMS-1, BCL2, RASSF1A, TERT, TNFRSF25, and EDNRB) in 18 bladder cancer cell lines, 127 bladder cancer samples, and 37 samples of adjacent normal bladder mucosa using the quantitative MethyLight assay. We also analyzed the methylation status in urine sediments of 20 cancer-free volunteers and 37 bladder cancer patients.Results: The 5 regions of DAPK, BCL2, TERT, RASS-FIA, and TNFRSF25 showed significant increases in methylation levels when compared with nonmalignant adjacent tissue (P < 0.01). Methylation levels of BCL2 were significantly associated with tumor staging and grading (P < 0.01), whereas methylation levels of RASSF1A and ARF were only associated with tumor stage (P < 0.04), and TERT methylation and EDNRB methylation were predictors of tumor grade (P < 0.02). To investigate clinical usefulness for noninvasive bladder cancer detection, we further analyzed the methylation status of the markers in urine samples of patients with bladder cancer. Methylation of DAPK, BCL2, and TERT in urine sediment DNA from bladder cancer patients was detected in the majority of samples (78%), whereas they were unmethylated in the urine sediment DNA from agematched cancer-free individuals.Conclusions: Our results indicate that methylation of the 5 region of apoptosis-associated genes is a common finding in patients with bladder carcinoma. The ability to detect methylation not only in bladder tissue, but also in urine sediments, suggests that methylation markers are promising tools for noninvasive detection of bladder cancers. Our results also indicate that some methylation markers, such as those in regions of RASSF1A and TNFRSF25, might be of limited use for detection because they are also methylated in normal bladder tissues.

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Section: Evaluation Of Methylation and Expression In Humanmentioning

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Detection of Methylated Apoptosis-Associated Genes in Urine Sediments of Bladder Cancer Patients

Friedrich

Weisenberger²,

Cheng³

et al. 2004

Clinical Cancer Research

204

178

View full text Add to dashboard Cite

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“…The EDNRB gene encodes the endothelin receptor type B, a protein with a role in potentiating vasoconstriction that is well established (47). The 5Ј regulatory region of the EDNRB gene contains a complex CpG island (48) and methylation at certain CpG dinucleotides in this island can lead to the silencing of this gene in these tissues (45). We have shown that EDNRB CpG island hypermethylation is a highly specific marker for prostate cancer that could become a useful clinical tool in assessing disease severity.…”

Section: Discussionmentioning

confidence: 93%

Hypermethylation of CpG Islands in Primary and Metastatic Human Prostate Cancer

Yegnasubramanian

Kowalski

Gonzalgo³

et al. 2004

Cancer Research

464

435

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Aberrant DNA methylation patterns may be the earliest somatic genome changes in prostate cancer. Using real-time methylation-specific PCR, we assessed the extent of hypermethylation at 16 CpG islands in DNA from seven prostate cancer cell lines (LNCaP, PC-3, DU-145, LAPC-4, CWR22Rv1, VCaP, and C42B), normal prostate epithelial cells, normal prostate stromal cells, 73 primary prostate cancers, 91 metastatic prostate cancers, and 25 noncancerous prostate tissues. We found that CpG islands at GSTP1, APC, RASSF1a, PTGS2, and MDR1 were hypermethylated in >85% of prostate cancers and cancer cell lines but not in normal prostate cells and tissues; CpG islands at EDNRB, ESR1, CDKN2a, and hMLH1 exhibited low to moderate rates of hypermethylation in prostate cancer tissues and cancer cell lines but were entirely unmethylated in normal tissues; and CpG islands at DAPK1, TIMP3, MGMT, CDKN2b, p14/ARF, and CDH1 were not abnormally hypermethylated in prostate cancers. Receiver operator characteristic curve analyses suggested that CpG island hypermethylation changes at GSTP1, APC, RASSF1a, PTGS2, and MDR1 in various combinations can distinguish primary prostate cancer from benign prostate tissues with sensitivities of 97.3-100% and specificities of 92-100%. Hypermethylation of the CpG island at EDNRB was correlated with the grade and stage of the primary prostate cancers. PTGS2 CpG island hypermethylation portended an increased risk of recurrence. Furthermore, CpG island hypermethylation patterns in prostate cancer metastases were very similar to the primary prostate cancers and tended to show greater differences between cases than between anatomical sites of metastasis.

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“…44 Typically, CpG islands are found at the 5′ ends of genes near the transcription start site often covering the promoter region, but such islands have also been identified far downstream of the transcription start site. 46,47 In several cases, it has been demonstrated that the methylation of islands remotely located from the transcription start site also results in gene silencing, [48][49][50] and both the methylation within exons as well as within introns has been shown to regulate gene expression. [51][52][53] In this regard, methylation of exon 1 of genes would be expected to be a common trend because CpG islands are often extended into the first exon and intron of a gene.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Silencing of ALDH1L1, a Metabolic Regulator of Cellular Proliferation, in Cancers

Oleinik

Krupenko

2011

Genes & Cancer

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FDH (10-formyltetrahydrofolate dehydrogenase, the product of the ALDH1L1 gene), a major folate-metabolizing enzyme in the cytosol, is involved in the regulation of cellular proliferation. We have previously demonstrated that FDH is strongly and ubiquitously down-regulated in malignant human tumors and cancer cell lines. Here, we report that promoter methylation is a major mechanism controlling FDH levels in human cancers. A computational analysis has identified an extensive CpG island in the ALDH1L1 promoter region. It contains 96 CpG pairs and covers the region between −525 and +918 bp of the ALDH1L1 gene including the promoter, the entire exon 1, and a part of intron 1 immediately downstream of the exon. Bisulfite sequencing analysis revealed extensive methylation of the island (76%-95% of CpGs) in cancer cell lines. In agreement with these findings, treatment of FDHdeficient A549 cells with the methyltransferase inhibitor 5-aza-2′-deoxycytidine restored FDH expression. Analysis of the samples from patients with lung adenocarcinomas demonstrated methylation of the ALDH1L1 CpG island in tumor samples and a total lack of methylation in respective normal tissues. The same phenomenon was observed in liver tissues: the CpG island was methylation free in DNA extracted from normal hepatocytes but was extensively methylated in a hepatocellular carcinoma. Levels of ALDH1L1 mRNA and protein correlated with the methylation status of the island, with tumor samples demonstrating down-regulation of expression or even complete silencing of the gene. Our studies have also revealed that exon 1 significantly increases transcriptional activity of ALDH1L1 promoter in a luciferase reporter assay. Interestingly, the exon is extensively methylated in samples with a strongly down-regulated or silenced ALDH1L1 gene. Keywords ALDH1L1, CpG island methylation, folate metabolism, lung adenocarcinomaOriginal Article

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The endothelin receptor B (EDNRB) promoter displays heterogeneous, site specific methylation patterns in normal and tumor cells

Cited by 90 publications

References 36 publications

Detection of Methylated Apoptosis-Associated Genes in Urine Sediments of Bladder Cancer Patients

Detection of Methylated Apoptosis-Associated Genes in Urine Sediments of Bladder Cancer Patients

Hypermethylation of CpG Islands in Primary and Metastatic Human Prostate Cancer

Epigenetic Silencing of ALDH1L1, a Metabolic Regulator of Cellular Proliferation, in Cancers

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