title: Tumor suppressor SCUBE2 inhibits breast-cancer cell migration and invasion through the reversal of epithelial-mesenchymal transition.
abstract: Signal peptide-CUB-EGF domain-containing protein 2 (SCUBE2) belongs to a secreted and membrane-associated multi-domain SCUBE protein family. We previously demonstrated that SCUBE2 is a novel breast-tumor suppressor and could be a useful prognostic marker. However, the role of SCUBE2 in breast-cancer cell migration and invasion and how it is regulated during the epithelial-mesenchymal transition (EMT) remain undefined. In this study, we showed that ectopic SCUBE2 overexpression could enhance the formation of E-cadherin-containing adherens junctions by β-catenin-SOX-mediated induction of forkhead box A1 (a positive regulator of E-cadherin) and upregulation of E-cadherin, which in turn led to epithelial transition and inhibited migration and invasion of aggressive MDA-MB-231 breast-carcinoma cells. SCUBE2 expression was repressed together with that of E-cadherin in TGF-β-induced EMT; direct expression of SCUBE2 alone was sufficient to inhibit the TGF-β-induced EMT. Furthermore, quantitative DNA methylation, methylation-specific PCR, and chromatin immunoprecipitation analyses revealed that SCUBE2 expression was inactivated by DNA hypermethylation at the CpG islands by recruiting and binding DNA methyltransferase 1 during TGF-β-induced EMT. Together, our results suggest that SCUBE2 plays a key role in suppressing breast-carcinoma-cell mobility and invasiveness by increasing the formation of the epithelial E-cadherin-containing adherens junctions to promote epithelial differentiation and drive the reversal of EMT.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, 114 Taiwan.
authors.forename: Yuh-Charn
authors.initials: YC
authors.lastname: Lin
authors.forename: Yi-Ching
authors.initials: YC
authors.lastname: Lee
authors.forename: Ling-Hui
authors.initials: LH
authors.lastname: Li
authors.forename: Chien-Jui
authors.initials: CJ
authors.lastname: Cheng
authors.forename: Ruey-Bing
authors.initials: RB
authors.lastname: Yang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D022005:Adherens Junctions / Q000187:drug effects / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D018899:CpG Islands; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D055747:SOX Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C495270:CTNNB1 protein, human; D015820:Cadherins; D002135:Calcium-Binding Proteins; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D008565:Membrane Proteins; C469999:SCUBE2 protein, human; D055747:SOX Transcription Factors; D016212:Transforming Growth Factor beta; D051176:beta Catenin; D008156:Luciferases; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases
keywords: Breast cancer; DNA hypermethylation; DNA methyltransferase; Epigenetic regulation; Epithelial–mesenchymal transition; Tumor suppressor