Long Noncoding RNA <i>ELIT-1</i> 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 (<i>ELIT-1</i>). <i>ELIT-1</i> was induced by TGFβ stimulation via the TGFβ/Smad pathway in TGFβ-responsive cell lines. <i>ELIT-1</i> depletion abrogated TGFβ-mediated EMT progression and expression of TGFβ target genes including <i>Snail</i>, a transcription factor critical for EMT. A positive correlation between high expression of <i>ELIT-1</i> and poor prognosis in patients with lung adenocarcinoma and gastric cancer suggests that <i>ELIT-1</i> may be useful as a prognostic and therapeutic target. RIP assays revealed that <i>ELIT-1</i> bound to Smad3, but not Smad2. In conjunction with Smad3, <i>ELIT-1</i> enhanced Smad-responsive promoter activities by recruiting Smad3 to the promoters of its target genes including <i>Snail</i>, other TGFβ target genes, and <i>ELIT-1</i> itself. Collectively, these data show that <i>ELIT-1</i> 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 <i>ELIT-1</i> and characterizes its role as a positive regulator of TGFβ/Smad3 signaling and EMT.<b>Graphical Abstract:</b> http://cancerres.aacrjournals.org/content/canres/79/11/2821/F1.large.jpg.