Role of DeltaNp63gamma in epithelial to mesenchymal transition.
Although members of the p63 family of transcription factors are known for their role in the development and differentiation of epithelial surfaces, their function in cancer is less clear. Here, we show that depletion of the ΔNp63α and β isoforms, leaving only ΔNp63γ, results in epithelial to mesenchymal transition (EMT) in the normal breast cell line MCF10A. EMT can be rescued by the expression of the ΔNp63α isoform. We also show that ΔNp63γ expressed in a background where all the other ΔNp63 are knocked down causes EMT with an increase in TGFβ-1, -2, and -3 and downstream effectors Smads2/3/4. In addition, a p63 binding site in intron 1 of TGFβ was identified. Inhibition of the TGFβ response with a specific inhibitor results in reversion of EMT in ΔNp63α- and β-depleted cells. In summary, we show that p63 is involved in inhibiting EMT and reduction of certain p63 isoforms may be important in the development of epithelial cancers.
Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, United Kingdom.
Jaime
J
Lindsay
Simon S
SS
McDade
Adam
A
Pickard
Karen D
KD
McCloskey
Dennis J
DJ
McCance
D001665:Binding Sites; D001943:Breast Neoplasms / Q000209:etiology / Q000473:pathology; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009375:Neoplasms, Glandular and Epithelial / Q000209:etiology; D020033:Protein Isoforms; D051785:Smad Proteins / Q000235:genetics*; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors; D016212:Transforming Growth Factor beta / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation
D020033:Protein Isoforms; D051785:Smad Proteins; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins