Epithelial cells acquire mesenchymal phenotypes through epithelial‐mesenchymal transition (EMT) during cancer progression. However, how epithelial cells retain their epithelial traits and prevent... Show moreEpithelial cells acquire mesenchymal phenotypes through epithelial‐mesenchymal transition (EMT) during cancer progression. However, how epithelial cells retain their epithelial traits and prevent malignant transformation is not well understood. Here, we report that the long noncoding RNA LITATS1 (LINC01137, ZC3H12A‐DT) is an epithelial gatekeeper in normal epithelial cells and inhibits EMT in breast and non‐small cell lung cancer cells. Transcriptome analysis identified LITATS1 as a TGF‐β target gene. LITATS1 expression is reduced in lung adenocarcinoma tissues compared with adjacent normal tissues and correlates with a favorable prognosis in breast and non‐small cell lung cancer patients. LITATS1 depletion promotes TGF‐β‐induced EMT, migration, and extravasation in cancer cells. Unbiased pathway analysis demonstrated that LITATS1 knockdown potently and selectively potentiates TGF‐β/SMAD signaling. Mechanistically, LITATS1 enhances the polyubiquitination and proteasomal degradation of TGF‐β type I receptor (TβRI). LITATS1 interacts with TβRI and the E3 ligase SMURF2, promoting the cytoplasmic retention of SMURF2. Our findings highlight a protective function of LITATS1 in epithelial integrity maintenance through the attenuation of TGF‐β/SMAD signaling and EMT. Show less
Li, Y.H.; Cui, C.; Xie, F.; Kielbasa, S.; Mei, H.L.; Dinther, M. van; ... ; Dijke, P. ten 2020
The transforming growth factor-beta (TGF-beta) family controls embryogenesis, stem cell differentiation, and tissue homeostasis. However, how post-translation modifications contribute to fine... Show moreThe transforming growth factor-beta (TGF-beta) family controls embryogenesis, stem cell differentiation, and tissue homeostasis. However, how post-translation modifications contribute to fine-tuning of TGF-beta family signaling responses is not well understood. Inhibitory (I)-Smads can antagonize TGF-beta/Smad signaling by recruiting Smurf E3 ubiquitin ligases to target the active TGF-beta receptor for proteasomal degradation. A proteomic interaction screen identified Vpr binding protein (VprBP) as novel binding partner of Smad7. Mis-expression studies revealed that VprBP negatively controls Smad2 phosphorylation, Smad2-Smad4 interaction, as well as TGF-beta target gene expression. VprBP was found to promote Smad7-Smurf1-T beta RI complex formation and induce proteasomal degradation of TGF-beta type I receptor (T beta RI). Moreover, VprBP appears to stabilize Smurf1 by suppressing Smurf1 poly-ubiquitination. In multiple adult and mouse embryonic stem cells, depletion of VprBP promotes TGF-beta or Activin-induced responses. In the mouse embryo VprBP expression negatively correlates with mesoderm marker expression, and VprBP attenuated mesoderm induction during zebrafish embryogenesis. Our findings thereby uncover a novel regulatory mechanism by which Smurf1 controls the TGF-beta and Activin cascade and identify VprBP as a critical determinant of embryonic mesoderm induction. Show less
