CDH1 (gene)

Cadherin-1 also known as CAM 120/80 or epithelial cadherin (E-cadherin) or uvomorulin is a is_associated_with::protein that in humans is encoded by the CDH1 is_associated_with::gene. CDH1 has also been designated as CD324 (is_associated_with::cluster of differentiation 324). It is a is_associated_with::tumor suppressor gene.

Function
Cadherin-1 is a classical member of the is_associated_with::cadherin superfamily. The encoded protein is a calcium-dependent cell-cell adhesion glycoprotein composed of five extracellular cadherin repeats, a transmembrane region, and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid, and ovarian cancers. Loss of function is thought to contribute to progression in cancer by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells, and the cytoplasmic domain is required for internalization. Identified transcript variants arise from mutation at consensus splice sites.

E-cadherin (epithelial) is the most well-studied member of the is_associated_with::cadherin family. It consists of 5 cadherin repeats (EC1 ~ EC5) in the extracellular domain, one transmembrane domain, and an intracellular domain that binds is_associated_with::p120-catenin and is_associated_with::beta-catenin. The is_associated_with::intracellular domain contains a highly-phosphorylated region vital to beta-catenin binding and, therefore, to E-cadherin function. Beta-catenin can also bind to alpha-catenin. Alpha-catenin participates in regulation of is_associated_with::actin-containing cytoskeletal filaments. In epithelial cells, E-cadherin-containing cell-to-cell junctions are often adjacent to actin-containing filaments of the is_associated_with::cytoskeleton.

E-cadherin is first expressed in the 2-cell stage of mammalian development, and becomes phosphorylated by the 8-cell stage, where it causes compaction. In adult tissues, E-cadherin is expressed in is_associated_with::epithelial tissues, where it is constantly regenerated with a 5-hour half-life on the cell surface. Cell-cell interactions mediated by E-cadherin are crucial to is_associated_with::blastula formation in many animals.

Clinical significance
Loss of E-cadherin function or expression has been implicated in is_associated_with::cancer progression and is_associated_with::metastasis. E-cadherin downregulation decreases the strength of cellular adhesion within a tissue, resulting in an increase in cellular motility. This in turn may allow cancer cells to cross the is_associated_with::basement membrane and invade surrounding tissues. E-cadherin is also used by pathologists to diagnose different kinds of breast cancer. When compared with invasive ductal carcinoma, E-cadherin expression is markedly reduced or absent in the great majority of is_associated_with::invasive lobular carcinomas when studied by is_associated_with::immunohistochemistry.

Interactions
CDH1 (gene) has been shown to interact with


 * is_associated_with::CBLL1,
 * is_associated_with::CDC27,
 * is_associated_with::CDON,
 * CDH3,
 * is_associated_with::C-Met,
 * CTNNB1,
 * CTNNA1
 * is_associated_with::FOXM1,
 * is_associated_with::HDAC1,
 * HDAC2,
 * is_associated_with::IQGAP1,
 * is_associated_with::FYN,
 * is_associated_with::NEDD9,
 * is_associated_with::Plakoglobin,
 * is_associated_with::Vinculin,


 * PTPmu(is_associated_with::PTPRM)
 * PTPrho(is_associated_with::PTPRT)

Cadherin-1 in metastasis
Transitions between epithelial and mesenchymal states play important roles in embryonic development and cancer metastasis. E-cadherin level changes in EMT (is_associated_with::epithelial-mesenchymal transition) and MET (is_associated_with::mesenchymal-epithelial transition). E-cadherin acts as an invasion suppressor and a classical tumor suppressor gene in pre-invasive lobular breast carcinoma.

1. E-cadherin in EMT:

E-cadherin is a crucial type of cell-cell adhesion to hold the epithelial cells tight together. E-cadherin can sequester β-catenin on the cell membrane by the cytoplasmic tail of E-cadherin. Loss of E-cadherin expression results in releasing β-catenin into the cytoplasm. Liberated β-catenin molecules may migrate into the nucleus and trigger the expression of EMT-inducing transcription factors. Together with other mechanisms, such as constitutive RTK activation, E-cadherin loss can lead cancer cells to the mesenchymal state and undergo metastasis. E-cadherin is an important switch in EMT.

2. E-cadherin in MET:

The mesenchymal state cancer cells migrate to new sites and may undergo METs in certain favorable microenvironment. For example, the cancer cells can recognize differentiated epithelial cell features in the new sites and upregulate E-cadherin expression. Those cancer cells can form cell-cell adhesions again and return to an epithelial state.

Cancer examples

 * Inactivation of CDH1 (accompany with loss of the wild-type allele) in 56% of lobular breast carcinomas.


 * Inactivation of CDH1 in 50% of diffuse gastric carcinomas.


 * Complete loss of E-cadherin protein expression in 84% of lobular breast carcinomas.

Genetic and epigenetic control of CDH1
Several proteins such as SNAI1/SNAIL, ZFHX1B/SIP1, SNAI2/SLUG,  TWIST1 and DeltaEF1 have been found to downregulate E-cadherin expression. When expression of those transcription factors is altered, transcriptional repressors of E-cadherin were overexpressed in tumor cells. Another group of genes, such as AML1, p300 and HNF3, can upregulate the expression of E-cadherin.

In order to study the epigenetic regulation of E-cadherin, M Lombaerts et al. performed a genome wide expression study on 27 human mammary cell lines. Their results revealed two main clusters that have the fibroblastic or epithelial phenotype, respectively. In close examination, the clusters showing fibroblast phenotypes only have either partial or complete CDH1 promoter methylation, while the clusters with epithelial phenotypes have both wild-type cell lines and cell lines with mutant CDH1 status. The authors also found that EMT can happen in breast cancer cell lines with hypermethylation of CDH1 promoter, but in breast cancer cell lines with a CDH1 mutational inactivation EMT cannot happen. It contradicts the hypothesis that E-cadherin loss is the initial or primary cause for EMT. In conclusion, the results suggest that “E-cadherin transcriptional inactivation is an epi-phenomenon and part of an entire program, with much more severe effects than loss of E-cadherin expression alone”.

Other studies also show that epigenetic regulation of E-cadherin expression occurs during metastasis. The methylation patterns of the E-cadherin 5’ CpG island are not stable. During metastatic progression of many cases of epithelial tumors, a transient loss of E-cadherin is seen and the heterogeneous loss of E-cadherin expression results from a heterogeneous pattern of promoter region methylation of E-cadherin.