LncRNA LITATS1 suppresses TGF-β-induced EMT and cancer cell plasticity by potentiating TβRI degradation.

Autor: Fan C; Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands.; Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands., Wang Q; Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands.; Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands., Kuipers TB; Department of Biomedical Data Sciences, Sequencing Analysis Support Core, Leiden University Medical Center, Leiden, The Netherlands., Cats D; Department of Biomedical Data Sciences, Sequencing Analysis Support Core, Leiden University Medical Center, Leiden, The Netherlands., Iyengar PV; Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands.; Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands., Hagenaars SC; Department of Surgery, Leiden University Medical Centre, Leiden, The Netherlands., Mesker WE; Department of Surgery, Leiden University Medical Centre, Leiden, The Netherlands., Devilee P; Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.; Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands., Tollenaar RAEM; Department of Surgery, Leiden University Medical Centre, Leiden, The Netherlands., Mei H; Department of Biomedical Data Sciences, Sequencing Analysis Support Core, Leiden University Medical Center, Leiden, The Netherlands., Ten Dijke P; Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands.; Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands.
Jazyk: angličtina
Zdroj: The EMBO journal [EMBO J] 2023 May 15; Vol. 42 (10), pp. e112806. Date of Electronic Publication: 2023 Mar 30.
DOI: 10.15252/embj.2022112806
Abstrakt: Epithelial 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.
(© 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)
Databáze: MEDLINE
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