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TWIST1-induced microRNA-424 drives an intermediate epithelial-to-mesenchymal transition that opposes metastasis

ABSTRACT: Epithelial-to-mesenchymal transition (EMT) is a dynamic process that relies on cellular plasticity; an EMT/MET axis is critical for metastatic colonization of carcinomas. Unlike epithelial programming, regulation of mesenchymal programming is not well understood in EMT. Here we describe the first microRNA that enhances exclusively mesenchymal programming. We demonstrate that microRNA-424 is up-regulated early during a TWIST1/SNAI1-induced EMT, and that it causes cells to express mesenchymal genes without affecting epithelial genes, resulting in a mixed/intermediate EMT. Further, microRNA-424 increases motility, decreases adhesion and induces a growth arrest, changes associated with a complete EMT. Patient microRNA-424 levels positively associate with TWIST1/2 and EMT-like gene signatures and is increased in primary tumors versus matched normal breast. However, microRNA-424 is down-regulated in metastases versus matched primary tumors. Correspondingly, microRNA-424 decreases tumor initiation and is post-transcriptionally down-regulated in macrometastases in mice. RNA-seq identified microRNA-424 regulates numerous genes associated with EMT and breast cancer stemness including the novel miR-424 target, TGFBR3, which regulates mesenchymal phenotypes without influencing miR-424 effects on tumor-initiating phenotypes; instead, we show that ERK signaling is critical for such tumor-initiating effects of miR-424. These findings suggest microRNA-424 plays distinct roles downstream of EMT-inducing factors, facilitating earlier stages, but repressing later stages, of metastasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE54505 | GEO | 2015/02/26

SECONDARY ACCESSION(S): PRJNA236738

REPOSITORIES: GEO

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TWIST1-induced microRNA-424 drives an intermediate epithelial-to-mesenchymal transition that opposes metastasis

Project description:Epithelial-to-mesenchymal transition (EMT) is a dynamic process that relies on cellular plasticity; an EMT/MET axis is critical for metastatic colonization of carcinomas. Unlike epithelial programming, regulation of mesenchymal programming is not well understood in EMT. Here we describe the first microRNA that enhances exclusively mesenchymal programming. We demonstrate that microRNA-424 is up-regulated early during a TWIST1/SNAI1-induced EMT, and that it causes cells to express mesenchymal genes without affecting epithelial genes, resulting in a mixed/intermediate EMT. Further, microRNA-424 increases motility, decreases adhesion and induces a growth arrest, changes associated with a complete EMT. Patient microRNA-424 levels positively associate with TWIST1/2 and EMT-like gene signatures and is increased in primary tumors versus matched normal breast. However, microRNA-424 is down-regulated in metastases versus matched primary tumors. Correspondingly, microRNA-424 decreases tumor initiation and is post-transcriptionally down-regulated in macrometastases in mice. RNA-seq identified microRNA-424 regulates numerous genes associated with EMT and breast cancer stemness including the novel miR-424 target, TGFBR3, which regulates mesenchymal phenotypes without influencing miR-424 effects on tumor-initiating phenotypes; instead, we show that ERK signaling is critical for such tumor-initiating effects of miR-424. These findings suggest microRNA-424 plays distinct roles downstream of EMT-inducing factors, facilitating earlier stages, but repressing later stages, of metastasis. Examination of mRNA levels in MCF12A human breast cell lines that stably over-expressed miR-424 or an empty vector (EV) control. Each group has three replicates.

2015-02-26 | E-GEOD-54505 | biostudies-arrayexpress

MET after transient Twist activation results in de novo gain of malignant traits

Project description:During Epithelial-Mesenchymal Transition (EMT), apical-basal polarized epithelial cells are converted to front-to-back polarized mesenchymal cells that only form loose cell-cell adhesions. These phenotypic changes are accompanied by acquisition of increased motility and invasiveness. EMT programs are orchestrated by pleiotropic transcription factors (TFs), such as Twist1 and Snail1 and effect morphogenetic steps during embryogenesis, including mesoderm formation and neural crest migration. EMTs have also been implicated in the acquisition of aggressive traits by carcinoma cells, including the ability to complete several steps of the metastatic cascade as well as propagation of the tumor by single cells (clonogenicity), a defining trait of tumor-initiating or cancer stem cells. However, the molecular links between the expression of EMT-TFs, the process of EMT and acquisition of clonogenicity remain obscure. Using inducible Twist1 or Snail1 expressed in CD24-positive mammary epithelial cells, we show that clonal growth in anchorage independence and EMT are induced sequentially and independently: clonogenic potential is induced prior to EMT and requires transient TF-activity. By contrast, EMT depends on continuous TF-activation over a longer period. In 3D-collagen assays, continuous Twist1 activity suppresses colony formation, whereas transient activation induces highly invasive growth independently of EMT. In conclusion, our results demonstrate that transient Twist1 activation suffices to drive tumor progression of CD24-positive breast epithelial cells, assessed by invasive as well as anchorage-independent clonal growth, whereas chronic Twist1 exposure can suppress these traits of aggressive tumor cells. We performed gene expression microarray analysis on CD24high and CD24negative populations derived from HMLE-Twist1-ER or HMLE-Snail1-ER cell lines upon various culture conditions

2015-07-02 | E-GEOD-61206 | biostudies-arrayexpress

MET after transient Twist activation results in de novo gain of malignant traits

2015-07-02 | GSE61206 | GEO

Zeb1 and Snail1 engage miR-200f transcriptional and epigenetic regulation during EMT

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)

2014-09-09 | E-GEOD-61217 | biostudies-arrayexpress

E-GEOD-54505

Project description:TWIST1-induced microRNA-424 drives an intermediate epithelial-to-mesenchymal transition that opposes metastasis

2019-05-14 | E-GEOD-54505 | ExpressionAtlas

RNA-seq of two human mammary epithelial cell lines (HMLE and HMLE-Twist-ER) treated with 4-hydroxytamoxifen vs control

Project description:Immortalized non-cancerous human mammary epithelial cells (HMLE) were transfected to express the murine fusion protein Twist1-estrogen receptor(point mutation G525R) (HTER). Twist1-mediated gene expression is activated by stimulation with 4-hydroxytamoxifen for several days and induces an epithelial-mesenchymal transition (EMT) in HTER cells. In breast cancer, EMT equips cancer cells for metastasis and therapy resistance. As control, HTER cells were treated with vehicle (methanol). As additional controls, HMLE cells were stimulated with 4-hydroxytamoxifen or methanol, respectively. Prior to RNA sequencing, EMT-undergoing HTER cells were sorted by fluorescence-activated cell sorting (FACS) based on E-Cadherin and CD44 surface protein levels into three populations, epithelial (E), hybrid epithelial-mesenchymal (EM), and mesenchymal (M): E-Cadherin_high_CD44_low (E), E-Cadherin_medium_CD44_medium (EM), and E-Cadherin_low_CD44_high (M).

2021-03-24 | E-MTAB-9365 | biostudies-arrayexpress

ChipSeq of Twist1 and YY1 in PLC-PRF-5 cells

Project description:Epithelial–mesenchymal transition (EMT) is an important mechanism of metastasis and malignant progression of hepatocellular carcinoma (HCC). However, the transcriptional regulation mechanism of EMT remains poorly understood. Some transcriptional co-activators can form phase-separated condensates at super-enhancers that compartmentalize and concentrate the transcription apparatus to drive robust gene expression. Here, we demonstrate that Twist1 and YY1, interact with p300 and form phase-separated local high-concentration interaction hubs at super-enhancers of miRNA-9 and activate its expression to induce EMT and promote the malignant evolution of HCC. Phase separation disrupted by metformin perturbs Twist–YY1 condensates, thereby inhibiting EMT. To explore how the Twist1 complex regulates miR-9 expression by binding SE region, we performed Twist1 ChIP-seq combined with H3K4me3, H3K4me1, H3K27ac, DNAse, p300, and YY1 ChIP-seq data to detect the SEs of miR-9. After metformin treatment, the peak of Twist1/YY1 on miR-9 SE decreased. Metformin specifically affects the binding of Twist1/YY1 to the miR-9 SE region. 1,6-hexanediol, as an aliphatic alcohol, can weaken hydrophobic interactions and inhibit liquid–liquid phase separation by disrupting hydrophobic interactions. In order to prove Twist1/YY1 interaction at these sites requires phase separation, we detect the accessibility of miR-9 SE regions in 1,6-hexanediol-treated cells. The result showed a general decrease in the accessibility of miR-9 super-enhancer regions in 1,6-hexanediol-treated cells and Twist1 / YY1 combines the SE region of miR-9 in the form of phase separation.

2019-12-13 | GSE141965 | GEO

ATAC-seq profiling of open chromatin in PLC-PRF cells

2019-12-13 | GSE141964 | GEO

TWIST1-induced microRNA-424 drives an intermediate epithelial-to-mesenchymal transition that opposes metastasis

Project description:Using a TWIST1-inducible epithelial-to-mesenchymal transition (EMT) model in HMLE cells, miRNA changes were profiled at different time points during an active EMT.

2015-02-26 | GSE58560 | GEO

TWIST1 methylation by SETD6 selectively antagonizes LINC-PINT expression in Glioblastoma multiforme

Project description:Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor among adults, which is characterized by high invasion, migration and proliferation abilities. One important process that contributes to the invasiveness of GBM is the epithelial to mesenchymal transition (EMT). EMT is regulated by a set of defined transcription factors which tightly regulate this process, among them is the basic helix-loop-helix family member, TWIST1. Here we show that TWIST1 is methylated on lysine-33 at chromatin by SETD6, a methyltransferase with expression levels correlating with poor survival in GBM patients. RNA-seq analysis in U251 GBM cells suggested that both SETD6 and TWIST1 regulate cell adhesion and migration processes. We further show that TWIST1 methylation attenuates the expression of the long-non-coding RNA, LINC-PINT, thereby suppressing EMT in GBM. Mechanistically, TWIST1 methylation represses the transcription of LINC-PINT by increasing the occupancy of EZH2 and the catalysis of the repressive H3K27me3 mark at the LINC-PINT locus. Under un-methylated conditions, TWIST1 dissociates from the LINC-PINT locus, allowing the expression of LINC-PINT which leads to increased cell adhesion and decreased cell migration. Together, our findings unravel a new mechanistic dimension for selective expression of LINC-PINT mediated by TWIST1 methylation.

2022-08-12 | PXD029361 | Pride

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