Abstract
Down-regulation of the epithelial cell-cell adhesion molecule E-cadherin is frequently associated with tumor formation and progression. Besides its role in physical cell-cell adhesion, E-cadherin is also thought to be involved in intracellular signaling in normal epithelial cells. In these cells, the Armadillo catenin p120ctn binds to the cytoplasmic domain of E-cadherin and stabilizes the adhesion complexes. On loss of E-cadherin, cytoplasmic p120ctn might accumulate and contribute to tumor malignancy. We used suppression subtractive hybridization to search for genes regulated by E-cadherin expression. We isolated human Nanos1 as a transcript of which levels decrease on E-cadherin reexpression in a human breast cancer cell line. The hNanos1 protein bears a COOH-terminal (CCHC)(2) zinc finger domain and belongs to an evolutionarily conserved protein family sharing functions in germ cell development in both vertebrates and invertebrates. We found an inverse correlation between E-cadherin and hNanos1 expression in various cell lines and under diverse conditions. Conditional expression of hNanos1 in human colorectal DLD1 cancer cells functionally abolished cell-cell adhesion. It induced cytoplasmic translocation of p120ctn, as well as strong migratory and invasive properties. We also found that the NH(2)-terminal domain of hNanos1, which is conserved only among mammals, interacts with p120ctn. hNanos1 counteracted the stimulatory effect of p120ctn on cell protrusion formation. Together, these findings describe a new function for hNanos1 as a downstream effector of E-cadherin loss contributing to tumor progression. Targeting hNanos1 might be a promising strategy in the treatment of E-cadherin-negative tumors in particular.
Highlights
E-Cadherin is a major epithelial cell-cell adhesion molecule that functions as a tumor suppressor [1]
To identify genes the expression of which is modulated by E-cadherin expression, we conducted comparative transcriptome analysis of E-cadherin–negative and E-cadherin–positive cancer cell lines
Through suppression subtractive hybridization (SSH) analysis of the closely related human breast cancer cell line MDA-MB-231 and its E-cadherin– expressing counterpart, MDA2BE5.36 [11, 28], we isolated a 538-bp cDNA fragment the expression of which was lower in the E-cadherin–expressing cells
Summary
E-Cadherin is a major epithelial cell-cell adhesion molecule that functions as a tumor suppressor [1]. H-Catenin interacts tightly via its Armadillo repeats with the catenin binding domain of the COOH-terminal tail of E-cadherin and via its NH2terminal domain with a-catenin. This is essential for the formation of actin cytoskeleton-coupled cell junctions, the detailed mechanism is a matter of debate [6]. P120 catenin (p120ctn) associates via its Armadillo repeat region with the juxtamembrane domain of the E-cadherin cytoplasmic tail. The interactions of E-cadherin with p120ctn and h-catenin are necessary for dynamically regulating adequate cell-cell adhesion by modulating events such as cadherin clustering and the strength of the connection with the actin cytoskeleton One major function of p120ctn is to stabilize cadherin complexes at the cell membrane by controlling the entry of cadherins into the degradative endocytic pathway (reviewed in refs 7, 8)
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