Snail-induced down-regulation of DeltaNp63alpha acquires invasive phenotype of human squamous cell carcinoma.
p63 is a member of the p53 family and regulates crucial events in the formation of epithelial structures, but the role of p63 in tumor is unclear. We found that Snail-induced epithelial-to-mesenchymal transition (EMT) is accompanied by down-regulation of p63 in human squamous cell carcinomas (SCC). DeltaNp63alpha is the predominantly expressed p63 isoform in SCC cells. DeltaNp63 promoter activity required a CAAT/enhancer binding protein (C/EBP) binding element and was reduced remarkably by Snail. Down-regulation of DeltaNp63alpha and reduction of C/EBPalpha were observed in EMT phenotype cells, which exhibited invasive activity in vitro. p63 knockdown in cells enhanced invasive activity in the presence of E-cadherin. Conversely, forced expression of DeltaNp63alpha blocked invasive activity of cells with the EMT phenotype. These findings indicate that Snail down-regulates DeltaNp63alpha, leading to acquisition of the invasive phenotype by SCC. The invasive activity caused by down-regulation of DeltaNp63alpha does not require down-regulation of E-cadherin.
Higashikawa
Koichiro
K
Department of Oral and Maxillofacial Surgery, Division of Cervico-Gnathostomatology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan. khigashi@hiroshima-u.ac.jp
Yoneda
Shingo
S
Tobiume
Kei
K
Taki
Masayuki
M
Shigeishi
Hideo
H
Kamata
Nobuyuki
N
D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D015536:Down-Regulation; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008648:Mesoderm / Q000473:pathology; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D000071250:Snail Family Transcription Factors; D015534:Trans-Activators / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D014846:Vulvar Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology
D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; D004268:DNA-Binding Proteins; D000071250:Snail Family Transcription Factors; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins