Regulation of p63 isoforms by snail and slug transcription factors in human squamous cell carcinoma.
TP63 is a p53-related gene that contains two alternative promoters, which give rise to transcripts that encode proteins with (TAp63) or without (DeltaNp63) an amino-transactivating domain. Whereas the expression of p63 is required for proper development of epithelial structures, the role of p63 in tumorigenesis remains unclear. Here, we investigated the role of Snail and Slug transcription factors, known to promote epithelial-to-mesenchymal transitions during development and cancer, in the regulation of p63 isoforms in human squamous cell carcinoma (SCC). In the present study, we observed that the expressions of DeltaN and TAp63 isoforms were, respectively, down- and up-regulated by both Snail and Slug. However, the induction of TAp63 was not directly caused by these two transcription factors but resulted from the loss of DeltaNp63, which acts as dominant-negative inhibitor of TAp63. In SCC cell lines and cancer tissues, high expression of Snail and Slug was also significantly associated with altered p63 expression. Finally, we showed that DeltaNp63 silencing reduced cell-cell adhesion and increased the migratory properties of cancer cells. These data suggest that the disruption of p63 expression induced by Snail and Slug plays a crucial role in tumor progression. Therefore, p63 and its regulating factors could constitute novel prognosis markers in patients with SCC and attractive targets for the therapeutic modulation of neoplastic cell invasiveness.
Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, 4000 Liege, Belgium. M.Herfs@student.ulg.ac.be
Michael
M
Herfs
Pascale
P
Hubert
Meggy
M
Suarez-Carmona
Anca
A
Reschner
Sven
S
Saussez
Geert
G
Berx
Pierre
P
Savagner
Jacques
J
Boniver
Philippe
P
Delvenne
D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D020033:Protein Isoforms; D012878:Skin Neoplasms / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D015534:Trans-Activators / Q000737:chemistry*; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000737:chemistry*
D020033:Protein Isoforms; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins