A p53/miRNA-34 axis regulates Snail1-dependent cancer cell epithelial-mesenchymal transition.
Snail1 is a zinc finger transcriptional repressor whose pathological expression has been linked to cancer cell epithelial-mesenchymal transition (EMT) programs and the induction of tissue-invasive activity, but pro-oncogenic events capable of regulating Snail1 activity remain largely uncharacterized. Herein, we demonstrate that p53 loss-of-function or mutation promotes cancer cell EMT by de-repressing Snail1 protein expression and activity. In the absence of wild-type p53 function, Snail1-dependent EMT is activated in colon, breast, and lung carcinoma cells as a consequence of a decrease in miRNA-34 levels, which suppress Snail1 activity by binding to highly conserved 3' untranslated regions in Snail1 itself as well as those of key Snail1 regulatory molecules, including β-catenin, LEF1, and Axin2. Although p53 activity can impact cell cycle regulation, apoptosis, and DNA repair pathways, the EMT and invasion programs initiated by p53 loss of function or mutation are completely dependent on Snail1 expression. These results identify a new link between p53, miR-34, and Snail1 in the regulation of cancer cell EMT programs.
Department of Oral Pathology, Oral Cancer Research Institute, College of Dentistry, Yonsei University, Seoul 120-752, South Korea.
Nam Hee
NH
Kim
Hyun Sil
HS
Kim
Xiao-Yan
XY
Li
Inhan
I
Lee
Hyung-Seok
HS
Choi
Shi Eun
SE
Kang
So Young
SY
Cha
Joo Kyung
JK
Ryu
Dojun
D
Yoon
Eric R
ER
Fearon
R Grant
RG
Rowe
Sanghyuk
S
Lee
Christopher A
CA
Maher
Stephen J
SJ
Weiss
Jong In
JI
Yook
D017209:Apoptosis; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D018613:Microscopy, Confocal; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin