title: Stabilization of phenotypic plasticity through mesenchymal-specific DNA hypermethylation in cancer cells.
abstract: The epithelial-mesenchymal transition (EMT) has a crucial role in normal and disease processes including tumor progression. In this study, we first classified epithelial-like and mesenchymal-like oral squamous cell carcinoma (OSCC) cell lines based on expression profiles of typical EMT-related genes using a panel of 18 OSCC cell lines. Then, we performed methylation-based and expression-based analyses of components of the Wnt signaling pathway, and identified WNT7A and WNT10A as genes silenced by mesenchymal-specific DNA hypermethylation in OSCCs. A significant association was revealed between some clinicopathological findings and the DNA methylation status of WNT7A (normal vs tumor, P=0.007; T1-2 vs T3-4, P=0.040; I-III vs IV, P=0.016) and WNT10A (N0-N1 vs N2-N3, P=0.046) in the advanced stages of OSCC. Moreover, we found that E-cadherin expression in cancer cells may be positively regulated by WNT7A, whose expression is negatively regulated by mesenchymal-specific DNA hypermethylation or ZEB1 in mesenchymal-like OSCC cells. Our findings indicate that epithelial-specific gene silencing through mesenchymal-specific DNA hypermethylation may stabilize the phenotypic plasticity of cancer cells during EMT/MET.
authors.affiliation: Department of Molecular Cytogenetics, Medical Research Institute and School of Biomedical Science, Tokyo Medical and Dental University, Yushima Bunkyo-ku, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kurasawa
authors.forename: K
authors.initials: K
authors.lastname: Kozaki
authors.forename: A
authors.initials: A
authors.lastname: Pimkhaokham
authors.forename: T
authors.initials: T
authors.lastname: Muramatsu
authors.forename: H
authors.initials: H
authors.lastname: Ono
authors.forename: T
authors.initials: T
authors.lastname: Ishihara
authors.forename: N
authors.initials: N
authors.lastname: Uzawa
authors.forename: I
authors.initials: I
authors.lastname: Imoto
authors.forename: T
authors.initials: T
authors.lastname: Amagasa
authors.forename: J
authors.initials: J
authors.lastname: Inazawa
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000235:genetics*; D010641:Phenotype; D051153:Wnt Proteins / Q000235:genetics; D060449:Wnt Signaling Pathway
chemical_list: C484142:WNT10A protein, human; C092778:WNT7A protein, human; D051153:Wnt Proteins