DNA Methylation and Cancer

Das, P.; Singal, Rakesh

doi:10.1200/jco.2004.07.151

Cited by 1,102 publications

(801 citation statements)

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“…Certain genes, such as 14-3-3σ, RASSF1A and P16INK4a, are commonly methylated in multiple human cancers (Wajed et al, 2001;Pulukuri and Rao, 2006), whereas others show high frequencies of methylation only in specific tumors. One example is the GSTP1 gene that is highly methylated in breast and prostate cancers but is largely unmethylated in other types of tumors (Das and Singal, 2004;Esteller et al, 2001). …”

Section: Discussionmentioning

confidence: 99%

Epigenetic inactivation of the tissue inhibitor of metalloproteinase-2 (TIMP-2) gene in human prostate tumors

et al. 2007

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Gene silencing via CpG island methylation in the promoter region is one of the mechanisms by which tumor suppressor genes are inactivated in human cancers. Previous studies have shown that the TIMP-2 gene, which is an endogenous inhibitor of matrix metalloproteinases involved in cell invasion and tumorigenesis, is downregulated or silenced in a variety of human cancer cell lines. Here, we investigated the mechanism underlying TIMP-2 expression in prostate cancer cell lines and primary prostate tumor samples. We observed a strong correlation between promoter hypermethylation and lost expression of TIMP-2 gene, which was supported by other results demonstrating that promoter demethylation by 5-aza-2′-deoxycytidine and trichostatin A reactivated TIMP-2 and restored its expression in TIMP-2-silenced metastatic prostate cell lines. These result were further substantiated by a chromatin immunoprecipitation assay, showing the preferential binding of MeCP2 to methylated CpG island in TIMP-2-silenced metastatic prostate cell lines. In vitro Matrigel invasion assays showed that reexpression of TIMP-2 after a combined treatment with 5-aza and TSA in metastatic prostate cells resulted in a significant reduction of tumor cell invasion. Furthermore, CpG methylation of TIMP-2 promoter was also shown in primary prostate tumors that expressed decreased TIMP-2 protein levels. These results suggest that the downregulation of the TIMP-2 gene is associated with promoter methylation and that this may play an important role in prostate cancer progression during the invasive and metastatic stages of the disease.

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Section: Discussionmentioning

confidence: 99%

Epigenetic inactivation of the tissue inhibitor of metalloproteinase-2 (TIMP-2) gene in human prostate tumors

et al. 2007

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“…A hallmark of cancer is a paradoxical aberration of DNA methylation patterns, with a global loss of DNA methylation that coexists with regional hypermethylation of certain genes. 44 It has been proposed that hypermethylation and hypomethylation in cancer are independent processes, which target different programs at different stages in tumorigenesis. 45 Hypermethylation and silencing of genes that regulate proliferation are proposed to be critical for deregulated growth early in carcinogenesis, while hypomethylation and activation of other genes may be more important for metastasis.…”

Section: Discussionmentioning

confidence: 99%

Hypomethylation-induced expression of S100A4 in endometrial carcinoma

et al. 2007

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Expression of various S100 genes has been associated with clinically aggressive subtypes in a variety of different cancers. We hypothesized that S100A4 would be overexpressed in endometrial carcinoma compared to benign endometrium. Quantitative real-time RT-PCR (qRT-PCR) was used to quantify the mRNA level of S100A4 in benign endometrium (n ¼ 19), endometrioid adenocarcinoma (n ¼ 87), and non-endometrioid tumors (n ¼ 21). Immunohistochemistry was used to verify the results of qRT-PCR and to assess protein localization. Possible mechanisms of S100A4 gene regulation were also examined. S100A4 was overexpressed in the grade 3 endometrioid tumors, uterine papillary serous carcinoma, and uterine malignant mixed mü llerian tumor. Expression in grade 1 and grade 2 endometrioid tumors was comparable to that of normal endometrium, which was quite low. Expression was significantly higher in stage III and IV tumors compared with stage I. By immunohistochemistry, S100A4 was expressed in the tumor cell cytoplasm of poorly differentiated tumors, but was not detected in normal endometrial glandular epithelium. In benign endometrium, S100A4 expression was confined to stromal cells. S100A4 was not regulated by estrogen or progesterone, and its expression in tumors was not significantly correlated to estrogen receptor or progesterone receptor content. However, methylation of the S100A4 gene was detected in benign endometrium and grade 1 tumors with low S100A4 expression. In contrast, grade 3 endometrioid tumors with high S100A4 mRNA and protein expression showed no methylation of the gene. These methylation results were verified in endometrial cancer cell lines with differential baseline levels of S100A4 protein. These results suggest that hypomethylation is an important mechanism of regulating the expression of the S100A4 gene. These results support the emerging concept that hypomethylation may play a role in the upregulation of genes during later stages of tumorigenesis. Keywords: endometrial cancer; S100A gene family; S100A4; methylation Endometrial carcinoma is the most common malignant neoplasm of the female genital tract and the fourth most frequently diagnosed cancer in women, following cancers of the breast, lung, and colon. 1 On the basis of histological and clinical features, endometrial carcinoma has been classified into two types. 2-4 Type I tumors (approximately 80% of all endometrial carcinomas) are typically low-grade (grade 1 or grade 2) endometrioid adenocarcinoma, most of which are confined to the uterus and have a favorable prognosis. Type II tumors (approximately 20%) are comprised of uterine papillary serous carcinoma, malignant mixed mü llerian tumors, and clear cell carcinoma. The nature of high-grade (grade 3) endometrioid adenocarcinoma is more controversial, as a subset may behave more like the Type II tumors. Type II cancers are associated with extrauterine spread and carry a high mortality rate. Previous studies have documented interesting molecular differences between endometrioid and nonendometrioid ...

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“…In the proposed model (Figure 8e), several events concurrently lead to CoAA overexpression: the amplified CoAA coding region and basal promoter, the lost negative regulatory sequence, and a positive feedback activation of CoAA's own expression. The lost silencing sequences contain densely arranged Alu repeats, which might facilitate DNA rearrangment (Gibbons and Dugaiczyk, 2005), and contribute to CpG methylation-mediated gene silencing (Schmid, 1998;Das and Singal, 2004;Jasinska and Krzyzosiak, 2004;Caiafa and Zampieri, 2005). It would be important in future studies to understand the silencing roles associated with the CoAA regulatory sequence.…”

Section: Discussionmentioning

confidence: 99%