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A natural antisense transcript regulates Zeb2/Sip1 gene expression during Snail1-induced epithelial–mesenchymal transition

¹ Programa de Recerca en Càncer, Institut Municipal d’Investigació Mèdica (IMIM)-Hospital del Mar, Barcelona 08003, Spain; ² Servicio de Oncología Médica, Hospital Universitario Puerta de Hierro, Madrid 28035, Spain; ³ Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona 08003, Spain

Expression of Snail1 in epithelial cells triggers an epithelial–mesenchymal transition (EMT). Here, we demonstrate that the synthesis of Zeb2, a transcriptional repressor of E-cadherin, is up-regulated after Snail1-induced EMT. Snail1 does not affect the synthesis of Zeb2 mRNA, but prevents the processing of a large intron located in its 5'-untranslated region (UTR). This intron contains an internal ribosome entry site (IRES) necessary for the expression of Zeb2. Maintenance of 5'-UTR Zeb2 intron is dependent on the expression of a natural antisense transcript (NAT) that overlaps the 5' splice site in the intron. Ectopic overexpression of this NAT in epithelial cells prevents splicing of the Zeb2 5'-UTR, increases the levels of Zeb2 protein, and consequently down-regulates E-cadherin mRNA and protein. The relevance of these results is demonstrated by the strong association between NAT presence and conservation of the 5'-UTR intron in cells that have undergone EMT or in human tumors with low E-cadherin expression. Therefore, the results presented in this article reveal the existence of a NAT capable of activating Zeb2 expression, explain the mechanism involved in this activation, and demonstrate that this NAT regulates E-cadherin expression.

[Keywords: Zeb2/Sip1; EMT; Snail1; NAT; IRES]]

Received September 4, 2007; revised version accepted January 10, 2008.

⁵ Corresponding author.

E-MAIL agarcia{at}imim.es; FAX 34-93-316-0410.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.455708.

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