Long Noncoding RNA ELIT-1 Acts as a Smad3 Cofactor to Facilitate TGFβ/Smad Signaling and Promote Epithelial-Mesenchymal Transition.

Abstract

TGFβ is involved in various biological processes, including development, differentiation, growth regulation, and epithelial-mesenchymal transition (EMT). In TGFβ/Smad signaling, receptor-activated Smad complexes activate or repress their target gene promoters. Smad cofactors are a group of Smad-binding proteins that promote recruitment of Smad complexes to these promoters. Long noncoding RNAs (lncRNA), which behave as Smad cofactors, have thus far not been identified. Here, we characterize a novel lncRNA EMT-associated lncRNA induced by TGFβ1 (ELIT-1). ELIT-1 was induced by TGFβ stimulation via the TGFβ/Smad pathway in TGFβ-responsive cell lines. ELIT-1 depletion abrogated TGFβ-mediated EMT progression and expression of TGFβ target genes including Snail, a transcription factor critical for EMT. A positive correlation between high expression of ELIT-1 and poor prognosis in patients with lung adenocarcinoma and gastric cancer suggests that ELIT-1 may be useful as a prognostic and therapeutic target. RIP assays revealed that ELIT-1 bound to Smad3, but not Smad2. In conjunction with Smad3, ELIT-1 enhanced Smad-responsive promoter activities by recruiting Smad3 to the promoters of its target genes including Snail, other TGFβ target genes, and ELIT-1 itself. Collectively, these data show that ELIT-1 is a novel trans-acting lncRNA that forms a positive feedback loop to enhance TGFβ/Smad3 signaling and promote EMT progression. SIGNIFICANCE: This study identifies a novel lncRNA ELIT-1 and characterizes its role as a positive regulator of TGFβ/Smad3 signaling and EMT.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/11/2821/F1.large.jpg.