Variable promoter region CpG island methylation of the putative tumor suppressor gene Connexin 26 in breast cancer

Tan, Lorwai; Bianco, Tina; Dobrovic, Alexander

doi:10.1093/carcin/23.2.231

Cited by 75 publications

(49 citation statements)

References 24 publications

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“…Lack of Cx protein expression in our experiments in HeLa, CaSki and SiHa cells correlated with loss of mRNA, as determined by RT-PCR (data not shown), indicating transcriptional downregulation. Gene silencing by methylation has previously been described with Cx26 (Tan et al, 2002), Cx32 and Cx43 (Piechocki et al, 1999), and indeed specifically for Cx43 in HeLa cells (King et al, 2000a). As an alternative, possibly transient mechanism, loss of GJIC during in vitro progression of W12G appeared to be due to a failure of Cx43 to target to the membrane.…”

Section: Gjic-proficient Hela Cells Stably Transfected With Cx43mentioning

confidence: 74%

The relationship between connexins, gap junctions, tissue architecture and tumour invasion, as studied in a novel in vitro model of HPV-16-associated cervical cancer progression

et al. 2003

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Disruption of gap junctional intercellular communication (GJIC) and/or connexins (gap junction proteins) is frequently reported in malignant cell lines and tumours. Certain human papillomaviruses (HPV) associated with the development of cancers, especially of the cervix, have previously been reported to downregulate GJIC in vitro. There is also evidence for reduced gap junctions in cervical dysplasia. However, many squamous hyperproliferative conditions, including HPV-induced warts, often show extensive upregulation of certain connexins. The association between HPV and GJIC, and the mechanism and consequence of deregulated GJIC in cervical tumour progression, remains unclear. Therefore, using a variety of nonmalignant and malignant cell lines and an organotypic raft-culture system, we investigated the relationship between HPV, gap junctions and tumour progression. Established cervical tumour cell lines carrying HPV were unable to communicate via gap junctions (when assayed by dye-transfer techniques). This correlated with lack of connexin protein expression, while transfection with connexins 26 or 43 led to functional gap junction membrane plaques. On the other hand, immortal but nonmalignant cell lines that contained episomal or integrated HPV-16, but required feeder-layer and growth-factor support, were consistently well coupled, and expressed multiple connexins at membrane junctions. In vitro selection of feeder-layer and growth-factorindependent variants eventually lead to loss of GJIC, which correlated with loss of membrane and increased cytoplasmic connexin 43 localization. However, this was preceded by loss of differentiation and stromal invasion, as assayed on the organotypic raft-culture model. Using this model, a comparison between noncoupled, well-coupled and connexin-transfected cell lines revealed no firm correlation between GJIC and dysplasia, but GJIC appeared to favour increased stratification. These findings demonstrate that loss of GJIC is frequent, but appears to occur more as a consequence of, rather than being the cause of, epithelial dysplasia, and may be influenced by, but is not directly attributable to, HPV.

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Section: Gjic-proficient Hela Cells Stably Transfected With Cx43mentioning

confidence: 74%

The relationship between connexins, gap junctions, tissue architecture and tumour invasion, as studied in a novel in vitro model of HPV-16-associated cervical cancer progression

et al. 2003

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“…[36][37][38] Because the GJB2 promoter is extremely rich in CpG dinucleotides, hypermethylation of the GJB2 promoter is a mechanism of its inactivation in several human tumors. 39,40 In addition, aberrant localization of CX26 protein in colorectal cancer has also been observed. 41 The mechanism by which GJB2 acts as a tumor suppressor gene will require further study.…”

Section: Discussionmentioning

confidence: 99%

Profiling of selenomethionine responsive genes in colon cancer by microarray analysis

Goulet¹,

Watts²,

Lord³

et al. 2007

Cancer Biology & Therapy

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AbbreviAtioNs AbstrACtHigh-selenium containing yeast is being evaluated in clinical trials against colon polyp recurrence. However, the molecular targets for the anticancer effects of selenium remain unclear. Previous studies by our group demonstrated that selenomethionine-induced growth arrest appears to be mediated by activation of ERK and subsequent phosphorylation of RSK and histone H3. These results suggest that selenomethionine can alter gene expression. In the present study, we have used cDNA microarrays to determine whether gene expression differences exist in HCT116 colon cancer cells treated with selenomethionine. These experiments reveal statistically significant expression changes for 50 genes. Genes we found to increase with selenomethionine treatment include KLK6, ATOX1, SGK, GJB2, DAP-1, PLAU, VIM, DPYSL2, STC2 and PXN. Conversely, genes downregulated by selenomethionine include PRKACB, LIM, DEPP, MYC, CDH5, ELF3, VSNL1, SAT and EGLN3. Further analysis of those genes using chromatin immunoprecipitation experiments showed that phosphorylated histone H3 on serine 10 bound to the GJB2 promoter (connexin 26) or the serum glucocorticoid kinase promoter is increased with selenomethionine treatment. Cells overexpressing CX26 or DAP-1 displayed a reduced number of colonies which suggests that these two genes could play a functional role in the growth inhibitory effects of selenomethionine. These data support the notion that selenomethionine-induced growth inhibition is associated with global changes in gene expression. They also demonstrate that selenomethionine can modify chromatin state to alter gene transcription. Finally, our studies provide a practical foundation for the further development of biomarkers to monitor the efficacy of selenomethionine in clinical trials.

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“…Tan et al have reported that methylation of the promoter region of the Cx26 gene is likely to be an important mechanism in modulating the expression of Cx26 in breast cancer. 24 Another report showed that downregulation of Cx 26 in human lung cancer was also related to promoter methylation. 25 These results suggested that promoter methlyation might be a common mechanism for repression of connexin genes in various tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of connexin 43 in nasopharyngeal carcinoma cells is related to promoter methylation

et al. 2007

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Summary Down-regulation of Cx43 expression had been shown to occur in nasopharyngeal carcinoma cells. The present study was undertaken to estimate if methylation of the promoter region in Cx43 gene was responsible for the repression of Cx43 expression in the CNE-1 nasopharyngeal carcinoma cells. Calcein transfer and lucifer yellow transfer were detected to evaluate gap junction intercellular communication (GJIC) in CNE-1 cells. It was found that the control CNE-1 cells showed no fluorescent dye transfer. After treatment with DNA methyltransferase inhibitor 5-aza-CdR, fluorescent dye transfer between cells became obvious. RT-PCR and Western blot were performed to determine the expression of Cx43 gene. The control CNE-1 cells showed a low expression level of Cx43, whereas 5-aza-CdR-treated CNE-1 cells showed an enhanced level of Cx43 expression. Methylation-sensitive restriction enzyme and PCR analysis showed that the methylation of the Cx43 gene promoter region occurred in CNE-1 cells. In addition, treatment with 5-aza-CdR inhibited the growth (including anchorage-independent growth) of CNE-1 cells, and resulted in an accumulation of cells in G0/G1 phase. These results indicate the promoter methylation as an important role in inactivation of Cx43 in CNE-1 cells.

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Variable promoter region CpG island methylation of the putative tumor suppressor gene Connexin 26 in breast cancer

Cited by 75 publications

References 24 publications

The relationship between connexins, gap junctions, tissue architecture and tumour invasion, as studied in a novel in vitro model of HPV-16-associated cervical cancer progression

The relationship between connexins, gap junctions, tissue architecture and tumour invasion, as studied in a novel in vitro model of HPV-16-associated cervical cancer progression

Profiling of selenomethionine responsive genes in colon cancer by microarray analysis

Downregulation of connexin 43 in nasopharyngeal carcinoma cells is related to promoter methylation

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