ZEB1 is regulated by K811 acetylation to promote stability, NuRD complex interactions, EMT, and NSCLC metastasis
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ABSTRACT:
PROVIDER: PRJNA935395 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23490135_1.fastq.gz | Fastqsanger.gz | |||
| SRR23490135_2.fastq.gz | Fastqsanger.gz | |||
| SRR23490136_1.fastq.gz | Fastqsanger.gz | |||
| SRR23490136_2.fastq.gz | Fastqsanger.gz | |||
| SRR23490137_1.fastq.gz | Fastqsanger.gz |
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Project description:To understand the role of Zeb1 acetylation in regulating its function a Zeb1 acetyl-mimetic and acetyl-deficient mutant expressing NSCLC cell line was generated. We then performed gene expression profiling analysis using data obtained from RNA-seq of GFP-vector, Zeb1 wild-type, Zeb1 deficient, and Zeb1 mimetic.
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Project description:Using an in vitro model for malignant transformation of human bronchial epithelial cells (HBECs) we have found epithelial-to-mesenchymal transition (EMT) and expression of the EMT-transcription factor ZEB1 are early and critical events. Specifically, we found preexisting oncogenic mutations in TP53 and KRAS were required for HBECs to engage EMT machinery in response to microenvironmental (serum/TGFβ) or specific oncogenetic (MYC) EMT-inducing factors, which induce EMT through distinct TGFβ-dependent and vitamin D receptor (VDR)-dependent pathways, respectively, with both requiring ZEB1. Functional studies demonstrated ZEB1 causally promotes the malignant progression of HBECs and tumorigenicity of NSCLC and small cell lung cancer (SCLC) lines. Mechanistically ZEB1 directly represses ESRP1 leading to increased mesenchymal splicing of CD44, which drives a switch to CD44hi status and defines a highly transformed subpopulation. This was supported by finding ZEB1 is expressed in early-stage primary non-small cell lung cancers (NSCLC), as early as stage IB tumors, and its expression correlates with TNM stage. We conclude that: ZEB1-induced EMT and associated ESRP1 and CD44 molecular changes are important biomarkers for lung cancer pathogenesis; TGFβ and VDR are EMT chemoprevention targets; and as such, ZEB1 represents an important therapeutic target in NSCLC and SCLC.
2016-08-31 | GSE77925 | GEO
Project description:Cell plasticity is emerging as a key regulator of tumor progression and metastasis. During carcinoma dissemination epithelial cells undergo epithelial to mesenchymal transition (EMT) processes characterized by the acquisition of migratory/invasive properties, while the reverse, mesenchymal to epithelial transition (MET) process, is also essential for metastasis outgrowth. Different transcription factors, called EMT-TFs, including Snail, bHLH and Zeb families are drivers of the EMT branch of epithelial plasticity, and can be post-transcriptionally downregulated by several miRNAs, as the miR-200 family. The specific or redundant role of different EMT-TFs and their functional interrelations are not fully understood. To study the interplay between different EMT-TFs, comprehensive gain and loss-of-function studies of Snail1, Snail2 and/or Zeb1 factors were performed in the prototypical MDCK cell model system. We here describe that Snail1 and Zeb1 are mutually required for EMT induction while continuous Snail1 and Snail2 expression, but not Zeb1, is needed for maintenance of the mesenchymal phenotype in MDCK cells. In this model system, EMT is coordinated by Snail1 and Zeb1 through transcriptional and epigenetic downregulation of the miR-200 family. Interestingly, Snail1 is involved in epigenetic CpG DNA methylation of the miR-200 loci, essential to maintain the mesenchymal phenotype. The present results thus define a novel functional interplay between Snail and Zeb EMT-TFs in miR200f regulation providing a molecular link to their previous involvement in the generation of EMT process in vivo. Expression analysis of MDCK over-expression EMT-TF Analysis of 7 overexpression MDCK cells each of them using biological rpelicates (MDCK-E47, Snail2, Snail1, Twist1, Tiwst2, Zeb1, Zeb2)
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Project description:Cell plasticity is emerging as a key regulator of tumor progression and metastasis. During carcinoma dissemination epithelial cells undergo epithelial to mesenchymal transition (EMT) processes characterized by the acquisition of migratory/invasive properties, while the reverse, mesenchymal to epithelial transition (MET) process, is also essential for metastasis outgrowth. Different transcription factors, called EMT-TFs, including Snail, bHLH and Zeb families are drivers of the EMT branch of epithelial plasticity, and can be post-transcriptionally downregulated by several miRNAs, as the miR-200 family. The specific or redundant role of different EMT-TFs and their functional interrelations are not fully understood. To study the interplay between different EMT-TFs, comprehensive gain and loss-of-function studies of Snail1, Snail2 and/or Zeb1 factors were performed in the prototypical MDCK cell model system. We here describe that Snail1 and Zeb1 are mutually required for EMT induction while continuous Snail1 and Snail2 expression, but not Zeb1, is needed for maintenance of the mesenchymal phenotype in MDCK cells. In this model system, EMT is coordinated by Snail1 and Zeb1 through transcriptional and epigenetic downregulation of the miR-200 family. Interestingly, Snail1 is involved in epigenetic CpG DNA methylation of the miR-200 loci, essential to maintain the mesenchymal phenotype. The present results thus define a novel functional interplay between Snail and Zeb EMT-TFs in miR200f regulation providing a molecular link to their previous involvement in the generation of EMT process in vivo. Expression analysis of MDCK over-expression EMT-TF
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Project description:Background: Colorectal cancer (CRC) is an aggressive primary intestinal malignancy with the third-highest incidence and second-highest mortality among all cancer types worldwide. Transcription factors (TFs) regulate cell development and differentiation owing to their ability to recognize specific DNA sequences upstream of genes. Numerous studies have demonstrated a strong correlation between TFs, the etiology of tumors, and therapeutic approaches. Here, we aimed to explore prognosis-related TFs and comprehend their carcinogenic mechanisms, thereby offering novel insights into the diagnosis and management of CRC. Materials and methods: Differentially expressed TFs between CRC and normal tissues were identified leveraging The Cancer Genome Atlas database, Weighted correlation network analysis and Cox regression analysis were performed to identify prognosis-related TFs. The cellular functions of hub TF zinc finger E-box binding homeobox 1 (ZEB1) were determined using by 5-ethynyl-2'-deoxyuridine and cell invasion assays in CRC cells. RNA-sequencing, Kyoto Encyclopedia of Genes and Genomes enrichment, and gene set enrichment analyses were used to identify the cellular processes in which ZEB1 participates. Immunoaffinity purification, silver staining mass spectrometry, and a chromatin immunoprecipitation assay were conducted to search for proteins that might interact with ZEB1 and the target genes they jointly regulate. Results: Thirteen central TFs related to prognosis were identified through bioinformatics analysis techniques. Among these TFs, ZEB1 emerged as the TF most closely associated with CRC, as determined through a combination of regulatory network diagrams, survival curves, and phenotype analyses. ZEB1 promotes CRC cell growth by recruiting the NuRD(MTA1) complex, and the ZEB1/NuRD(MTA1) complex transcriptionally represses glycolysis-associated tumor suppressor genes. Conclusion: Our study not only identified a hub biomarker related to CRC prognosis but also revealed the specific molecular mechanisms through which ZEB1 affects cancer progression. These insights provide crucial evidence for the diagnosis of CRC and potential treatment opportunities.
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Project description:Multiple EMT-promoting/inhibiting transcription factors have been identified including Snail, Zeb1 and Ovol2. To understand differential roles of these factors, we performed gene expression profiling by RNA-seq upon Snail-/Zeb1-induced EMT or Ovol2-induced MET in human mammary epithelial MCF10A cells.
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Project description:We investigated the effect of miR-1199-5p, miR-200b-3p and miR-429-3p on gene expression profiles during TGFbeta-induced EMT in normal murine mammary gland cells by using the mRNA-sequencing. Our analysis demonstrates that miR-1199-5p and both miR-200 family members share only 6 target genes, indicating that besides regulating Zeb1 expression they exert distinct functions during EMT.
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