LncRNA LITATS1 suppresses TGF-β-induced EMT and cancer cell plasticity by potentiating TβRI degradation.
Humans
Carcinoma, Non-Small-Cell Lung
/ metabolism
Cell Line, Tumor
Cell Movement
Cell Plasticity
Epithelial-Mesenchymal Transition
/ genetics
Lung Neoplasms
/ metabolism
RNA, Long Noncoding
/ genetics
Transforming Growth Factor beta
/ metabolism
Ubiquitin-Protein Ligases
/ genetics
Receptor, Transforming Growth Factor-beta Type I
LINC01137
TGF-β type I receptor
ZC3H12A-DT
epithelial-mesenchymal transition
transforming growth factor-β
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
15 05 2023
15 05 2023
Historique:
revised:
28
02
2023
received:
13
10
2022
accepted:
02
03
2023
medline:
16
5
2023
pubmed:
31
3
2023
entrez:
30
3
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 36994542
doi: 10.15252/embj.2022112806
pmc: PMC10183827
doi:
Substances chimiques
RNA, Long Noncoding
0
SMURF2 protein, human
EC 2.3.2.26
Transforming Growth Factor beta
0
Ubiquitin-Protein Ligases
EC 2.3.2.27
Receptor, Transforming Growth Factor-beta Type I
EC 2.7.11.30
Banques de données
GEO
['GSE203119', 'GSE198393']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e112806Informations de copyright
© 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
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