N-cadherin gene expression in prostate carcinoma is modulated by integrin-dependent nuclear translocation of Twist1.
The gain of N-cadherin expression in carcinomas has been shown to be important in the regulation of cell migration, invasion, and survival. Here, we show that N-cadherin mRNA expression in PC-3 prostate carcinoma cells is dependent on beta(1) integrin-mediated cell adhesion to fibronectin and the basic helix-loop-helix transcription factor Twist1. Depletion of Twist1 mRNA by small interfering RNA resulted in decreased expression of both Twist1 and N-cadherin and the inhibition of cell migration. Whereas Twist1 gene expression was independent of beta(1) integrin-mediated adhesion, Twist1 protein failed to accumulate in the nuclei of cells cultured in anchorage-independent conditions. The increased nuclear accumulation of Twist1 following cell attachment was suppressed by treatment with an inhibitor of Rho kinase or a beta(1) integrin neutralizing antibody. The effect of Twist1 on induction of N-cadherin mRNA required an E-box cis-element located within the first intron (+2,627) of the N-cadherin gene. These data raise the possibility that integrin-mediated adhesion to interstitial matrix proteins during metastasis differentially regulates the nuclear/cytoplasmic translocation and DNA binding of Twist1, activating N-cadherin transcription.
Cancer Biology Graduate Interdisciplinary Program, and Department of Surgery, University of Arizona Health Sciences Center, 1501 North Campbell Avenue, Tucson, AZ 85724, USA.
Nelson R
NR
Alexander
Nhan L
NL
Tran
Harish
H
Rekapally
Carol E
CE
Summers
Carlotta
C
Glackin
Ronald L
RL
Heimark
D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics*; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D024721:E-Box Elements; D005353:Fibronectins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D007438:Introns; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D015533:Transcriptional Activation; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*
D015820:Cadherins; D005353:Fibronectins; D019012:Integrin beta1; D009687:Nuclear Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1