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Interactions between Twist and other core epithelial-mesenchymal transition factors are controlled by GSK3-mediated phosphorylation.

ABSTRACT: A subset of transcription factors classified as neural crest 'specifiers' are also core epithelial-mesenchymal transition regulatory factors, both in the neural crest and in tumour progression. The bHLH factor Twist is among the least well studied of these factors. Here we demonstrate that Twist is required for cranial neural crest formation and fate determination in Xenopus. We further show that Twist function in the neural crest is dependent upon its carboxy-terminal WR domain. The WR domain mediates physical interactions between Twist and other core epithelial-mesenchymal transition factors, including Snail1 and Snail2, which are essential for proper function. Interaction with Snail1/2, and Twist function more generally, is regulated by GSK-3-?-mediated phosphorylation of conserved sites in the WR domain. Together, these findings elucidate a mechanism for coordinated control of a group of structurally diverse factors that function as a regulatory unit in both developmental and pathological epithelial-mesenchymal transitions.

SUBMITTER: Lander R

PROVIDER: S-EPMC4198179 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Interactions between Twist and other core epithelial-mesenchymal transition factors are controlled by GSK3-mediated phosphorylation.

Lander Rachel R Nasr Talia T Ochoa Stacy D SD Nordin Kara K Prasad Maneeshi S MS Labonne Carole C

Nature communications 20130101

A subset of transcription factors classified as neural crest 'specifiers' are also core epithelial-mesenchymal transition regulatory factors, both in the neural crest and in tumour progression. The bHLH factor Twist is among the least well studied of these factors. Here we demonstrate that Twist is required for cranial neural crest formation and fate determination in Xenopus. We further show that Twist function in the neural crest is dependent upon its carboxy-terminal WR domain. The WR domain m ...[more]

PMID: 23443570

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Project description:BackgroundTwist-related protein 1 (TWIST1) plays an essential role in the carcinogenesis and metastasis of NSCLC. Our aims were to identify the molecule at the downstream of TWIST1 and to evaluate its potential as a diagnostic and a prognostic marker in NSCLC.MethodsThe functional genes at the downstream of TWIST1 were obtained via microarray gene expression analyses in the NSCLC cell line. The expression levels of synaptotagmin 7 (SYT7) in a cohort of patients with NSCLC (n = 154) were examined using immunohistochemistry staining and assessed by Kaplan-Meier survival analysis and Cox regression analysis. The effects of SYT7 on the tumorigenesis and metastasis of NSCLC were measured in NSCLC cells. In vivo xenograft lung cancer models were used to study the tumorigenesis role of SYT7.FindingsWe discovered that SYT7 is significantly altered by TWIST1 expression. We further confirmed that SYT7 protein was significantly higher in NSCLC than that in the adjacent normal lung tissue, and higher SYT7 expression was associated with poor survival of NSCLC patients. The protein level of SYT7 was positively correlated with TWIST1 in NSCLC tissue. Functional experiments indicated that SYT7 promoted proliferation, invasion, and metastasis and inhibited cell apoptosis of NSCLC cells in vitro. In vivo experiments showed that shSYT7 inhibited the xenograft tumor growth of NSCLC cells. Knocking down of SYT7 increased the expression of E-cadherin and decreased the level of N-cadherin and Vimentin in cultured cells.InterpretationOur data indicate that SYT7 is an important promoter for EMT and tumor progression in NSCLC. FUND: This project was supported by grants from the Major Scientific and Technological Innovation Project of Shandong Province (2018CXGC1212), Science and Technology Foundation of Shandong Province (2014GSF118084, 2016GSF121043), Medical and Health Technology Innovation Plan of Jinan City (201805002) and the National Natural Science Foundation of China (81372333).

Project description:BackgroundEpithelial-to-mesenchymal transition (EMT) is a key step of the progression of tumor cell metastasis. Recent work has demonstrated some miRNAs play critical roles in EMT. In this study, we focused on the roles of miR-300 in regulating EMT.MethodsThe expression levels of miR-300 were examined in epithelial carcinoma cells that underwent an EMT using quantitative reverse transcription-PCR. The role of miR-300 in EMT was investigated by transfection of the miR-300 mimic or inhibitor in natural epithelial-mesenchymal phenotype cell line pairs and in transforming growth factor (TGF) beta-induced EMT cell models. A luciferase reporter assay and a rescue experiment were conducted to confirm the target gene of miR-300. The efficacy of miR-300 against tumor invasion and metastasis was evaluated both in vitro and in vivo. Correlation analysis between miR-300 expression and the expression levels of its target gene, as well as tumor metastasis was performed in specimens from patients with head and neck squamous cell carcinoma (HNSCC).ResultsMiR-300 was found down-regulated in the HNSCC cells and breast cancer cells that underwent EMT. Ectopic expression of miR-300 effectively blocked TGF-beta-induced EMT and reversed the phenotype of EMT in HN-12 and MDA-MB-231 cells, but inhibition of miR-300 in the epithelial phenotype cells, HN-4 and MCF-7 cells, could induce EMT. The luciferase reporter assay and the rescue assay results showed that miR-300 directly targets the 3'UTR of Twist. Enforced miR-300 expression suppressed cell invasion in vitro and experimental metastasis in vivo. Clinically, miR-300 expression was found inversely correlated with Twist expression and reduced miR-300 was associated with metastasis in patient specimens.ConclusionsDown-regulation of miR-300 is required for EMT initiation and maintenance. MiR-300 may negatively regulate EMT by direct targeting Twist and therefore inhibit cancer cell invasion and metastasis, which implicates miR-300 as an attractive candidate for cancer therapy.

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Interactions between Twist and other core epithelial-mesenchymal transition factors are controlled by GSK3-mediated phosphorylation.

Publications

Interactions between Twist and other core epithelial-mesenchymal transition factors are controlled by GSK3-mediated phosphorylation.

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