Desmocollin switching in colorectal cancer

Khan, Kalyan; Hardy, Richard J.; Haq, Asif; Ogunbiyi, Olagunju; Morton, Dion; Chidgey, Martyn

doi:10.1038/sj.bjc.6603453

Cited by 75 publications

(82 citation statements)

References 16 publications

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“…We know that in the majority of colon cancers, DSC2 gene expression is lost, with the concomitant induction of DSC1 and DSC3 expression (7). We can speculate that the switch to DSC1 and DSC3 may foster EMT and an invasive phenotype.…”

Section: The Regulation Of the Dsc2 Gene May Provide Insights Into Dementioning

confidence: 99%

“…However, in several human cancers, there is a breakdown in this tissue-restricted expression pattern. It is believed that this ''desmocollin switching'' could be a component of EMT, similar to the well-described ''cadherin switching'' (6,7). The mechanisms regulating this change in desmocollin gene patterning are not known, although the switch from E-cadherin to N-cadherin seen with EMT is brought about by potent transcriptional repressors such as Slug or Snail that suppress E-cadherin gene expression (8,9).…”

Section: Introductionmentioning

confidence: 99%

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Repression of the Desmocollin 2 Gene Expression in Human Colon Cancer Cells Is Relieved by the Homeodomain Transcription Factors Cdx1 and Cdx2

Funakoshi

Ezaki

Kong

et al. 2008

Molecular Cancer Research

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Desmosomes are intracellular junctions that provide strong cell-cell adhesion in epithelia and cardiac muscle. Their disruption causes several human diseases and contributes to the epithelial-to-mesenchymal transition observed in cancer. Desmocollin 2 (DSC2) is a cadherin superfamily member and a critical component of desmosomes found in intestinal epithelium. However, the mechanism regulating DSC2 gene expression in intestinal cells is not known. Cdx1 and Cdx2 are homeodomain transcription factors that regulate intestine-specific gene expression. Cdx expression in the past has been associated with the induction of desmosomes. We now show that the DSC2 gene is a transcriptional target for Cdx1 and Cdx2. Colon cancer cell lines retaining Cdx2 expression typically express DSC2. Restoration of Cdx expression in Colo 205 cells induced DSC2 mRNA and protein and the formation of desmosomes. The 5 ¶-flanking region of the DSC2 promoter contains two consensus Cdx-binding sites. Electrophoretic mobility shift assays show that Cdx1 and Cdx2 bind these sites in vitro, and chromatin immunoprecipitation confirmed Cdx2 binding in vivo. DSC2 promoter truncations established that these regions are Cdx responsive. The truncations also identify a region of the promoter in which potent transcriptional repressors act. This repressor activity is relieved by Cdx binding. We conclude that the homeodomain transcription factors Cdx1 and Cdx2 regulate DSC2 gene expression in intestinal epithelia by reversing the actions of a transcriptional repressor. The regulation of desmosomal junctions by Cdx contributes to normal intestinal epithelial columnar morphology and likely antagonizes the epithelial-to-mesenchymal transition necessary for the metastasis of colon cancer cells in humans.

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Section: The Regulation Of the Dsc2 Gene May Provide Insights Into Dementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Repression of the Desmocollin 2 Gene Expression in Human Colon Cancer Cells Is Relieved by the Homeodomain Transcription Factors Cdx1 and Cdx2

Funakoshi

Ezaki

Kong

et al. 2008

Molecular Cancer Research

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“…In some cases, the immunohistochemistry data are contradictory and this may be at least in part due to the use of antibodies in early studies that do not distinguish between the various desmocollin and desmoglein gene products. Recent studies have shown loss of Dsg2 in gastric cancer (Biedermann et al, 2005;Yashiro et al, 2006), Dsc2 in colorectal cancer (Khan et al, 2006) and Dsc3 in breast cancer (as a result of promoter hypermethylation) (Oshiro et al, 2005). By contrast, Dsg2 and Dsg3 are overexpressed in squamous cell cancer of the skin (Kurzen et al, 2003) and head and neck cancer (Chen et al, 2007), respectively.…”

Section: Other Desmosomal Constituents Wnt/b-catenin Signalling and mentioning

confidence: 99%

Desmosomes: a role in cancer?

2007

Self Cite

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Much evidence now attests to the importance of desmosomes and their constituents in cancer. Alterations in the expression of desmosomal components could contribute to the progression of the disease by modifying intracellular signal transduction pathways and/or by causing reduced cell adhesion. The Wnt/b-catenin pathway is a potential target because of the involvement of the cytoplasmic desmosomal protein plakoglobin. Loss of desmosomal adhesion is a prerequisite for the epithelial -mesenchymal transition, implicated in the conversion of early stage tumours to invasive cancers.

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“…Along the same lines, DSC2 and DSC3 expression is downregulated in colorectal and breast cancer, respectively [44,45]; whereas DSG3 is overexpressed in squamous cell carcinoma and head and neck cancer [43,46]. In general, whether desmosomes are involved in cancer and metastasis is very poorly understood [47].…”

Section: Desmosomes and Cancermentioning

confidence: 99%

Broken hearts, woolly hair, and tattered skin: when desmosomal adhesion goes awry

Bazzi

Christiano

2007

Current Opinion in Cell Biology

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Desmosomal cadherins constitute the adhesive core of desmosomes. The different types of these cadherins are differentially expressed in a tissue specific as well as differentiation dependent manner. The skin and the heart are two examples of tissues whose vital functions require the ability to endure mechanical stress, and therefore, the integrity of desmosomal adhesion. When this adhesion is compromised via mutations in genes encoding desmosomal cadherins or associated plaque proteins, both tissues can suffer the consequences. Open questions revolve around whether the resulting phenotypes are solely due to physical disruption of cell adhesion, or whether these events are coupled with signaling mechanisms that influence many additional cellular processes. In this review, we focus on new developments in desmosomal adhesion with an emphasis on the skin, hair and heart.

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Desmocollin switching in colorectal cancer

Cited by 75 publications

References 16 publications

Repression of the Desmocollin 2 Gene Expression in Human Colon Cancer Cells Is Relieved by the Homeodomain Transcription Factors Cdx1 and Cdx2

Repression of the Desmocollin 2 Gene Expression in Human Colon Cancer Cells Is Relieved by the Homeodomain Transcription Factors Cdx1 and Cdx2

Desmosomes: a role in cancer?

Broken hearts, woolly hair, and tattered skin: when desmosomal adhesion goes awry

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