Stabilization of phenotypic plasticity through mesenchymal-specific DNA hypermethylation in cancer cells

• Published in: Oncogene Vol. 31; no. 15; pp. 1963 - 1974
• Main Authors: Kurasawa, Y, Kozaki, K, Pimkhaokham, A, Muramatsu, T, Ono, H, Ishihara, T, Uzawa, N, Imoto, I, Amagasa, T, Inazawa, J
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.04.2012; Nature Publishing Group
• Subjects: Adult; Aged; Aged, 80 and over; Apoptosis; c-Met protein; Cancer; Carcinoma, Squamous Cell - genetics; Cell Biology; Cell Line, Tumor; DNA; DNA Methylation; E-Cadherin; Epithelial-Mesenchymal Transition; Female; Gene expression; Gene Silencing; Genotype & phenotype; Human Genetics; Humans; Internal Medicine; Male; Medicine; Medicine & Public Health; Mesenchyme; Methylation; Middle Aged; Mouth Neoplasms - genetics; Oncology; Oral cancer; Oral carcinoma; Oral squamous cell carcinoma; original-article; Phenotype; Phenotypic plasticity; Physiological aspects; Signal transduction; Squamous cell carcinoma; Tumor cell lines; Tumors; Wnt protein; Wnt Proteins - genetics; Wnt Signaling Pathway; Japan; DNA hypermethylation; WNT7A; WNT10A; oral squamous cell carcinoma; EMT
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2011.373

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.