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

  1. Manuel Beltran1,
  2. Isabel Puig1,4,
  3. Cristina Peña2,
  4. José Miguel García2,
  5. Ana Belén Álvarez1,
  6. Raúl Peña1,
  7. Félix Bonilla2, and
  8. Antonio García de Herreros1,3,5
  9. 1 Programa de Recerca en Càncer, Institut Municipal d’Investigació Mèdica (IMIM)-Hospital del Mar, Barcelona 08003, Spain;
  10. 2 Servicio de Oncología Médica, Hospital Universitario Puerta de Hierro, Madrid 28035, Spain;
  11. 3 Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona 08003, Spain

Abstract

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.

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