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

• Published in: The EMBO journal 2023-05, Vol.42 (10), p.e112806-n/a
• Main Authors: Fan, Chuannan, Wang, Qian, Kuipers, Thomas B, Cats, Davy, Iyengar, Prasanna Vasudevan, Hagenaars, Sophie C, Mesker, Wilma E, Devilee, Peter, Tollenaar, Rob A E M, Mei, Hailiang, ten Dijke, Peter
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Breast; Carcinoma, Non-Small-Cell Lung - metabolism; Cell Line, Tumor; Cell migration; Cell Movement; Cell Plasticity; Degradation; EMBO03; EMBO36; Epithelial cells; Epithelial-Mesenchymal Transition - genetics; epithelial‐mesenchymal transition; Epithelium; Extravasation; Gene expression; Humans; Life Sciences; LINC01137; Lung cancer; Lung Neoplasms - metabolism; Mammary gland; Mammary glands; Non-coding RNA; Non-small cell lung carcinoma; Phenotypes; Prognosis; Proteasomes; Receptor, Transforming Growth Factor-beta Type I; Ribonucleic acid; RNA; RNA, Long Noncoding - genetics; Signaling; Smad protein; TGF‐β type I receptor; Transcriptomes; Transforming Growth Factor beta - metabolism; Transforming growth factor-b; transforming growth factor‐β; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Xenotransplantation; ZC3H12A‐DT
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.2022112806

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. Synopsis Epithelial‐mesenchymal transition (EMT) endows malignant cells with critical invasive properties, yet mechanisms controlling its induction remain poorly understood. This study identifies long noncoding RNA (lncRNA) LITATS1 as a protective gatekeeper of epithelial cell identity and antagonist of TGF‐β‐induced EMT. Transcriptome analysis of human mammary gland cells identifies LITATS1 as a TGF‐β targeted epithelial lncRNA. LITATS1 expression correlates with better prognosis in breast and non‐small cell lung cancer patients. LITATS1 inhibits basal and TGF‐β‐induced EMT, cancer cell migration, and extravasation in xenografts. LITATS1 attenuates TGF‐β/SMAD signaling by enhancing TβRI proteasomal degradation. LITATS1 serves as a scaffold stabilizing interactions between TβRI and E3 ligase SMURF2, potentiating TβRI polyubiquitination. Graphical Abstract Long noncoding RNA LITATS1 safeguards epithelial cell identity by inhibiting epithelial‐mesenchymal transition.