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E-Cadherin Regulates Human Nanos1, Which Interacts With Research Article E-Cadherin Regulates Human Nanos1, which Interacts with p120ctn and Induces Tumor Cell Migration and Invasion Kristin Strumane,1,3 Arnaud Bonnomet,4 Christophe Stove,1 Roosmarijn Vandenbroucke,1 Beatrice Nawrocki-Raby,4 Erik Bruyneel,2 Marc Mareel,2 Philippe Birembaut,4 Geert Berx,1 and Frans van Roy1 1Department for Molecular Biomedical Research, VIB and Ghent University, Ghent, Belgium; 2Laboratory of Experimental Cancerology, Ghent University Hospital, Ghent, Belgium; 3The Netherlands Cancer Institute, Amsterdam, the Netherlands; and 4Institut National de la Sante´et de la Recherche Medicale U514, Institut Fe´de´ratifde Recherche 53, and Laboratoire Pol Bouin, Centre Hospitalier Universitaire Maison Blanche, Reims, France Abstract by direct binding to cytoplasmic Armadillo catenins (5). h-Catenin Down-regulation of the epithelial cell-cell adhesion molecule interacts tightly via its Armadillo repeats with the catenin binding domain of the COOH-terminal tail of E-cadherin and via its NH2- E-cadherin is frequently associated with tumor formation and a progression. Besides its role in physical cell-cell adhesion, terminal domain with -catenin. This is essential for the formation E-cadherin is also thought to be involved in intracellular of actin cytoskeleton-coupled cell junctions, although the detailed signaling in normal epithelial cells. In these cells, the mechanism is a matter of debate (6). In addition, p120 catenin Armadillo catenin p120ctn binds to the cytoplasmic domain (p120ctn) associates via its Armadillo repeat region with the juxtamembrane domain of the E-cadherin cytoplasmic tail. The of E-cadherin and stabilizes the adhesion complexes. On loss h of E-cadherin, cytoplasmic p120ctn might accumulate and interactions of E-cadherin with p120ctn and -catenin are necessary for dynamically regulating adequate cell-cell adhesion contribute to tumor malignancy. We used suppression subtractive hybridization to search for genes regulated by by modulating events such as cadherin clustering and the strength E-cadherin expression. We isolated human Nanos1 as a of the connection with the actin cytoskeleton (reviewed in ref. 5). transcript of which levels decrease on E-cadherin reexpression One major function of p120ctn is to stabilize cadherin complexes in a human breast cancer cell line. The hNanos1 protein bears at the cell membrane by controlling the entry of cadherins into the degradative endocytic pathway (reviewed in refs 7, 8). a COOH-terminal (CCHC)2 zinc finger domain and belongs to an evolutionarily conserved protein family sharing functions The molecular basis of the suppressive signals that are conferred in germ cell development in both vertebrates and inverte- by functional expression of E-cadherin on cancer cells has not been brates. We found an inverse correlation between E-cadherin fully elucidated. Loss of E-cadherin might induce signaling by h and hNanos1 expression in various cell lines and under catenins released from the cell membrane. Indeed, -catenin is also diverse conditions. Conditional expression of hNanos1 in a major component of the canonical Wnt signaling pathway human colorectal DLD1 cancer cells functionally abolished (reviewed in refs. 5, 9). When the Wnt signaling pathway is turned h cell-cell adhesion. It induced cytoplasmic translocation of on (e.g., by certain gene mutations in cancer), cytoplasmic - p120ctn, as well as strong migratory and invasive properties. catenin becomes protected from proteasomal degradation, trans- locates to the nucleus, binds LEF/Tcf, and acts as an oncogenic We also found that the NH2-terminal domain of hNanos1, which is conserved only among mammals, interacts with transcription cofactor. However, in the absence of such mutations h p120ctn. hNanos1 counteracted the stimulatory effect of or of a Wnt signal, the -catenin that is released from the p120ctn on cell protrusion formation. Together, these findings membrane on cadherin loss is rapidly degraded. Cadherins are describe a new function for hNanos1 as a downstream effector both necessary and sufficient for localization of p120ctn at the cell of E-cadherin loss contributing to tumor progression. Target- membrane (10). Cadherin deficiency does not significantly alter ing hNanos1 might be a promising strategy in the treatment of p120ctn levels but leaves it stranded in the cytoplasm and/or the E-cadherin–negative tumors in particular. (Cancer Res 2006; nucleus (10–12). In the cytoplasm, p120ctn interacts with Rho 66(20): 10007-15) GTPases (reviewed in refs. 7, 8, 13). It directly binds, via its Armadillo repeats, to RhoA and inhibits its activity by acting as a Introduction guanine nucleotide dissociation inhibitor. p120ctn also indirectly activates Rac1 and Cdc42 through guanine nucleotide exchange E-Cadherin is a major epithelial cell-cell adhesion molecule that factors such as Vav-2. The combined effects of cytoplasmic p120ctn functions as a tumor suppressor (1). Moreover, E-cadherin promote cell migration and, consequently, invasion and metastasis. deficiency plays a causative role in tumor cell invasion and In the nucleus, p120ctn can interact with the transcription factor metastasis (2–4). The extracellular domains of the transmembrane Kaiso, and it is likely that this also contributes to the malignant E-cadherin molecules form homophilic adhesion dimers stabilized phenotype (14, 15). Here, we describe the identification of human Nanos1 as a transcript that is down-regulated by E-cadherin. The human Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Nanos 1 gene encodes a (CCHC)2 zinc finger protein that is highly Requests for reprints: Frans van Roy, Department for Molecular Biomedical homologous to the Nanos orthologues in Drosophila and mouse, Research, VIB-Ghent University, Technologiepark 927, B-9052 Ghent-Zwijnaarde, which are known to have an evolutionarily conserved function in Belgium. Phone: 32-9-331-3604; Fax: 32-9-331-3500; E-mail: [email protected]. I2006 American Association for Cancer Research. embryonic patterning and germ line development (16–22). Our doi:10.1158/0008-5472.CAN-05-3096 finding that E-cadherin regulates the expression of hNanos1 in www.aacrjournals.org 10007 Cancer Res 2006; 66: (20). October 15, 2006 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2006 American Association for Cancer Research. Cancer Research carcinoma cells prompted us to seek a functional link between E- 2 mmol/L L-glutamine, 100 units/mLpenicillin, and 100 Ag/mLstrepto- cadherin and hNanos1 in epithelial cells. We generated cell systems mycin. The HEK293T cell line was obtained from the American Cell with inducible expression of hNanos1 and found that hNanos1 Type Culture Collection (Rockville, MD) and maintained in DMEM supple- impairs E-cadherin function in cell-cell adhesion and promotes cell mented with 5% FCS, 5% newborn bovine serum, 2 mmol/L L-glutamine, 0.4 mmol/Lsodium pyruvate, 100 units/mLpenicillin and 100 Ag/mL motility and invasion. Interestingly, we found that hNanos1 streptomycin. DLD1TR21-Teton cells, also called DLD1-Teton, were kindly interacts with the Armadillo protein p120ctn and counteracts the provided by Dr. H. Clevers (Hubrecht Laboratory, Utrecht, the Netherlands) effect of its overexpression on cell protrusion formation. and cultured in RPMI with 10% FCS. SW480 and transfected derivatives, kindly provided by Dr. Schwarte-Waldhoff (Ruhr-Universitat Bochum, Bochum, Germany) (24, 25), were maintained in DMEM supplemented Materials and Methods with 10% FCS and 100 units/mLpenicillin and 100 Ag/mLstreptomycin. Suppression subtractive hybridization and cloning of hNanos1. Generation of stable inducible cell systems. DLD1-Teton cells were Polyadenylated mRNA, obtained from subconfluent human E-cadherin– stably transfected with linearized pcDNA4/TO-Myc-hNanos1 by electro- negative MDA-MB-231 breast cancer cells and a derivative transfected cell poration. Clones were isolated after 2 weeks of selection in 500 Ag/mL line reexpressing E-cadherin, was isolated with the Fast Track 2.0 Kit zeocin and 10 Ag/mLblasticidin (Invitrogen). Expression was induced with (Invitrogen, Merelbeke, Belgium), in accordance with the recommendations doxycycline (1 Ag/mL; Sigma, St. Louis, MO) for 48 hours. of the manufacturer. cDNA subtraction was done using the PCR-select Immunofluorescence assays. Methanol fixation and immunofluores- cDNA subtraction kit (BD Biosciences Clontech, Erembodegem, Belgium). cence were done following standard procedures (11). The specific The subtracted cDNA libraries, generated by subcloning the PCR products antibodies used were mouse monoclonal antibody (mAb) 9E10 against the in the pGEM-T vector (Promega, Madison, WI), were screened for Myc-tag (dilution 1:500; Sigma), mouse mAb clone 36 against E-cadherin differentially expressed cDNAs using plus/minus colony hybridization. (1:100; Transduction Laboratories, Lexington, United Kingdom), mouse Finally, the differential expression of isolated clones was confirmed by mAb clone 14 against h-catenin (1:500; Transduction Laboratories), and Northern blotting. mouse mAb pp120ctn against p120ctn (1:500; Transduction Laboratories). The 538-bp hNanos1 cDNA fragment isolated in the suppression sub- The secondary antibody used was Alexa 594–coupled antimouse immuno- tractive hybridization (SSH) screen was used to probe a fetal kidney phage globulin (1:200; Molecular Probes, Eugene, OR). Nuclei were stained with cDNA library
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