p120-catenin is transcriptionally downregulated by FOXC2 in non-small cell lung cancer cells.
p120-catenin (p120ctn) plays a major role in cell adhesion and motility through the regulation of E-cadherin and interaction with RhoGTPase and Rac1. p120ctn is downregulated in several malignancies including non-small cell lung cancer (NSCLC). Here, we investigated transcriptional regulation of p120ctn in NSCLC. We cloned a 1,400-bp amplicon of chromosome 11 from position -1,082 to +320 relative to the transcription start site into a firefly luciferase reporter vector and prepared serial deletion constructs to pinpoint cis-acting elements involved in the regulation of p120ctn. We transfected NSCLC cell lines and immortalized normal human respiratory epithelial cells with the abovementioned constructs. We found reduced p120ctn promoter activity, protein level, and mRNA message in lung cancer cells compared with noncancerous immortalized lung epithelial cells. Serial deletion analysis of p120ctn promoter identified a region between positions +267 and +282, which mediated the transcriptional repression of p120ctn. This region harbored putative binding sites for FOXC2 and FOXL1 transcription factors. Direct binding of FOXC2 to the p120ctn promoter between positions +267 and +282 was confirmed by electromobility shift assay. RNAi-mediated silencing of FOXC2 in A549, H157, and H358 cells resulted in increasing p120ctn promoter activity as well as mRNA and protein levels. Finally, silencing FOXC2 in these NSCLC cells enhanced E-cadherin level, which was reversed by simultaneous silencing of p120ctn. In summary, our data support the notion that FOXC2 mediates the transcriptional repression of p120ctn in NSCLC.
Mortazavi
Fariborz
F
Division of Hematology/Oncology, Veterans Administration, Greater Los Angeles, West Los Angeles, California, USA. fredmortazavi@ucla.edu
An
Jiabin
J
Dubinett
Steven
S
Rettig
Matthew
M
D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051177:Catenins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference / Q000502:physiology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D012097:Repressor Proteins / Q000235:genetics; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic / Q000235:genetics*; D000095002:Delta Catenin
D051177:Catenins; C491001:FOXL1 protein, human; D051858:Forkhead Transcription Factors; D012333:RNA, Messenger; D012097:Repressor Proteins; C082078:mesenchyme fork head 1 protein; D000095002:Delta Catenin; C000722347:CTNND1 protein, human