A Genome-Wide Search Identifies Epigenetic Silencing of Somatostatin, Tachykinin-1, and 5 Other Genes in Colon Cancer

Mori, Yuriko; Cai, Kedan; Cheng, Yulan; Wang, Suna; Paun, Bogdan C.; Hamilton, James P.; Jin, Zhe; Sato, Fumiaki; Berki, Agnes; Kan, Takatsugu; Ito, Takahiro; Mantzur, Carmit; Abraham, John M.; Meltzer, Stephen J.

doi:10.1053/j.gastro.2006.06.006

Cited by 169 publications

(195 citation statements)

References 31 publications

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“…Therefore, we examined whether v-Src-mediated down-regulation of SSeCKS transcription was controlled by epigenetic mechanisms. Indeed, previous reports indicated that AKAP12/Gravin is inactivated by promoter hypermethylation in gastric and colon cancer (12,32). RT-PCR analysis showed that treatment of v-Src/3T3 cells with the DNA methyltransferase inhibitor, 5-aza-C, failed to restore the steady mRNA levels of either isoform of SSeCKS (Fig.…”

Section: Vsr Activity Correlates With Changes In Chromatin Structure-mentioning

confidence: 80%

v-Src-mediated Down-regulation of SSeCKS Metastasis Suppressor Gene Promoter by the Recruitment of HDAC1 into a USF1-Sp1-Sp3 Complex

Gelman

2007

Journal of Biological Chemistry

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SSeCKS (Src-suppressed C kinase substrate), also called gravin/AKAP12, is a large scaffolding protein with metastasis suppressor activity. Two major isoforms of SSeCKS are expressed in most cell and tissue types under the control of two independent promoters, designated ␣ and ␤, separated by 68 kb. SSeCKS transcript and protein levels are severely decreased in Src-and Ras-transformed fibroblasts and in many epithelial tumors. By dissecting its promoters with progressive deletion analysis, we identified the sequence between ؊106 and ؊49 in the ␣ proximal promoter as the minimal v-Src-responsive element, which contains E-and GC-boxes bound by USF1 and Sp1/ Sp3, respectively. Both E-and GC-boxes are crucial for v-Srcresponsive and basal promoter activities. v-Src does not alter USF1 binding levels at the E-box, but it increases Sp1/Sp3 binding to the GC-box despite no change in their cellular protein abundance. SSeCKS ␣ and ␤ transcript levels in v-Src/3T3 cells can be restored by treatment with the histone deacetylase inhibitor, trichostatin A, but not with the DNA demethylation agent, 5-azacytidine. Chromatin changes are found only on the ␣ promoter even though the ␤ proximal promoter contains a similar E-and GC-box arrangement. Recruitment of HDAC1 is necessary and sufficient to cause repression of ␣ proximal promoter activity, and the addition of Sp1 and/or Sp3 potentiates the repression. Our data suggest that suppression of the ␤ promoter is facilitated by Src-induced changes in the ␣ promoter chromatinization mediated by a USF1-Sp1-Sp3 complex.

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Section: Vsr Activity Correlates With Changes In Chromatin Structure-mentioning

confidence: 80%

v-Src-mediated Down-regulation of SSeCKS Metastasis Suppressor Gene Promoter by the Recruitment of HDAC1 into a USF1-Sp1-Sp3 Complex

Gelman

2007

Journal of Biological Chemistry

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“…The former group, although apparently not frequently methylated in primary tumours, might be considered as candidate genes implicated in progression (assuming that acquisition of methylation in cell culture might have a growth advantage). In this context, it is interesting to note that PTGS1 methylation is frequent in prostate cancer (Bastian et al, 2005), THY1 has been implicated as a candidate TSG in nasopharyngeal cancer (Lung et al, 2005) and SST promoter methylation has been described in B90% of colorectal cancers (Mori et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Functional epigenomics approach to identify methylated candidate tumour suppressor genes in renal cell carcinoma

et al. 2008

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Promoter region hypermethylation and transcriptional silencing is a frequent cause of tumour suppressor gene (TSG) inactivation in many human cancers. Previously, to identify candidate epigenetically inactivated TSGs in renal cell carcinoma (RCC), we monitored changes in gene expression in four RCC cell lines after treatment with the demethylating agent 5-azacytidine. This enabled us to identify HAI-2/SPINT2 as a novel epigenetically inactivated candidate RCC TSG. To identify further candidate TSGs, we undertook bioinformatic and molecular genetic evaluation of a further 60 genes differentially expressed after demethylation. In addition to HAI-2/ SPINT2, four genes (PLAU, CDH1, IGFB3 and MT1G) had previously been shown to undergo promoter methylation in RCC. After bioinformatic prioritisation, expression and/or methylation analysis of RCC cell lines ± primary tumours was performed for 34 genes. KRT19 and CXCL16 were methylated in RCC cell lines and primary RCC; however, 22 genes were differentially expressed after demethylation but did not show primary tumour-specific methylation (methylated in normal tissue (n ¼ 1); methylated only in RCC cell lines (n ¼ 9) and not methylated in RCC cell lines (n ¼ 12)). Re-expression of CXCL16 reduced growth of an RCC cell line in vitro. In a summary, a functional epigenomic analysis of four RCC cell lines using microarrays representing 11 000 human genes yielded both known and novel candidate TSGs epigenetically inactivated in RCC, suggesting that this is valid strategy for the identification of novel TSGs and biomarkers.

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“…Biomarkers can be used to predict prognosis and optimise therapeutic strategies. Hypermethylation of the MAL promoter has been shown in colorectal and oesophageal cancers and MAL has been proposed as a putative tumour suppressor in these cancer types (Mimori et al, 2003;Kazemi-Noureini et al, 2004;Mori et al, 2006). Moreover, it has been proposed as a candidate marker for early detection of these cancers, as methylation of MAL could already be detected in precursor lesions (Lind et al, 2007(Lind et al, , 2008Mimori et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…In other gastrointestinal cancers, that is, colorectal and oesophageal cancer, the T-lymphocyte maturation associated protein MAL, involved in glycolipid-enriched membrane-mediated apical transport, has been described to be inactivated by promoter hypermethylation (Puertollano and Alonso, 1999;Mimori et al, 2003;Kazemi-Noureini et al, 2004;Mori et al, 2006;Lind et al, 2007). Promoter hypermethylation of MAL was a frequent event in these two cancer types, but infrequent in normal mucosa.…”

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confidence: 99%

MAL promoter hypermethylation as a novel prognostic marker in gastric cancer

et al. 2008

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T-lymphocyte maturation associated protein, MAL, has been described as a tumour-suppressor gene with diagnostic value in colorectal and oesophageal cancers, and can be inactivated by promoter hypermethylation. The aim of this study was to analyse the prevalence of MAL promoter hypermethylation and the association with mRNA expression in gastric cancers and to correlate methylation status to clinicopathological data. Bisulphite-treated DNA isolated from formalin-fixed and paraffin-embedded samples of 202 gastric adenocarcinomas and 22 normal gastric mucosae was subjected to real-time methylation-specific PCR (Q-MSP). Two regions within the MAL promoter (M1 and M2) were analysed. In addition, 17 frozen gastric carcinomas and two gastric cancer cell lines were analysed both by Q-MSP and real-time RT -PCR. Methylation of M1 and M2 occurred in 71 and 80% of the gastric cancers, respectively, but not in normal gastric mucosa tissue. Hypermethylation of M2, but not M1, correlated with significantly better disease-free survival in a univariate (P ¼ 0.03) and multivariate analysis (P ¼ 0.03) and with downregulation of expression (P ¼ 0.01). These results indicate that MAL has a putative tumour-suppressor gene function in gastric cancer, and detection of promoter hypermethylation may be useful as a prognostic marker.

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A Genome-Wide Search Identifies Epigenetic Silencing of Somatostatin, Tachykinin-1, and 5 Other Genes in Colon Cancer

Cited by 169 publications

References 31 publications

v-Src-mediated Down-regulation of SSeCKS Metastasis Suppressor Gene Promoter by the Recruitment of HDAC1 into a USF1-Sp1-Sp3 Complex

v-Src-mediated Down-regulation of SSeCKS Metastasis Suppressor Gene Promoter by the Recruitment of HDAC1 into a USF1-Sp1-Sp3 Complex

Functional epigenomics approach to identify methylated candidate tumour suppressor genes in renal cell carcinoma

MAL promoter hypermethylation as a novel prognostic marker in gastric cancer

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