title: The human cadherin 11 is a pro-apoptotic tumor suppressor modulating cell stemness through Wnt/β-catenin signaling and silenced in common carcinomas.
abstract: Genetic alterations of 16q21-q22, the locus of a 6-cadherin cluster, are frequently involved in multiple tumors, suggesting the presence of critical tumor suppressor genes (TSGs). Using 1 Mb array comparative genomic hybridization (aCGH), we refined a small hemizygous deletion (~1 Mb) at 16q21-22.1, which contains a single gene Cadherin-11 (CDH11, OB-cadherin). CDH11 was broadly expressed in human normal adult and fetal tissues, while its silencing and promoter CpG methylation were frequently detected in tumor cell lines, but not in immortalized normal epithelial cells. Aberrant methylation was also frequently detected in multiple primary tumors. CDH11 silencing could be reversed by pharmacologic or genetic demethylation, indicating an epigenetic mechanism. Ectopic expression of CDH11 strongly suppressed tumorigenecity and induced tumor cell apoptosis. Moreover, CDH11 was found to inhibit Wnt/β-catenin and AKT/Rho A signaling, as well as actin stress fiber formation, thus further inhibiting tumor cell migration and invasion. CDH11 also inhibited epithelial-to-mesenchymal transition and downregulated stem cell markers. Thus, our work identifies CDH11 as a functional tumor suppressor and an important antagonist of Wnt/β-catenin and AKT/Rho A signaling, with frequent epigenetic inactivation in common carcinomas.
authors.affiliation: Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong and CUHK Shenzhen Research Institute, Hong Kong.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: J
authors.initials: J
authors.lastname: Ying
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: X
authors.initials: X
authors.lastname: Shu
authors.forename: Y
authors.initials: Y
authors.lastname: Fan
authors.forename: J
authors.initials: J
authors.lastname: Tan
authors.forename: Y
authors.initials: Y
authors.lastname: Cao
authors.forename: S W
authors.initials: SW
authors.lastname: Tsao
authors.forename: G
authors.initials: G
authors.lastname: Srivastava
authors.forename: A T C
authors.initials: AT
authors.lastname: Chan
authors.forename: Q
authors.initials: Q
authors.lastname: Tao
mesh_terms: D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D055028:Comparative Genomic Hybridization / Q000379:methods; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D018613:Microscopy, Confocal; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D015820:Cadherins; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins; D051176:beta Catenin; C086960:osteoblast cadherin