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N-cadherin Gene Expression in Prostate Carcinoma Is Modulated by Integrin-Dependent Nuclear Translocation of Twist1

¹ Cancer Biology Graduate Interdisciplinary Program, and ² Departments of Surgery, and Cell Biology and Anatomy, University of Arizona Health Sciences Center, Tucson, Arizona; ³ Translational Genomics Institute, Phoenix, Arizona; and ⁴ Division of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, California

Requests for reprints: Ronald L. Heimark, University of Arizona Health Sciences Center, 1501 North Campbell Avenue, P.O. Box 245112, Tucson, AZ 85724. Phone: 520-626-1913; Fax: 520-626-9118; E-mail: rheimark{at}u.arizona.edu.

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 ß₁ 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 ß₁ 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 ß₁ 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 Res 2006; 66(7): 3365-9)

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