A Hierarchical Regulatory Landscape during the Multiple Stages of EMT

Meyer-Schaller, Nathalie; Cardner, Mathias; Diepenbruck, Maren; Saxena, Mohit; Tiede, Stefanie; Lüönd, Fabiana; Ivánek, Robert; Beerenwinkel, Niko; Christofori, Gerhard

doi:10.1016/j.devcel.2018.12.023

Cited by 68 publications

(84 citation statements)

References 39 publications

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“…FOXA and SMAD proteins, AP4, and PBX3 are transcription factors with roles in EMT suppression and execution . Therefore, the conversion of epithelial into mesenchymal gene expression likely follows a gradual and hierarchical pattern whereby core EMT TFs trigger sequential changes in the activity of an expanding number of signalling pathways and TFs . An intriguing question is whether the same EMT executioner mechanisms operate regardless of cellular background …”

Section: Discussionmentioning

confidence: 99%

“…14,24,[47][48][49] Therefore, the conversion of epithelial into mesenchymal gene expression likely follows a gradual and hierarchical pattern whereby core EMT TFs trigger sequential changes in the activity of an expanding number of signalling pathways and TFs. 50 An intriguing question is whether the same EMT executioner mechanisms operate regardless of cellular background. 50 Similar to mSNAIL1, mLEF1 overexpression produced G1/S cell cycle arrest and impaired tumour growthremarkable effects considering that LS174T cells harbour oncogenic versions of β-Catenin and KRAS.…”

Section: Discussionmentioning

confidence: 99%

“…50 An intriguing question is whether the same EMT executioner mechanisms operate regardless of cellular background. 50 Similar to mSNAIL1, mLEF1 overexpression produced G1/S cell cycle arrest and impaired tumour growthremarkable effects considering that LS174T cells harbour oncogenic versions of β-Catenin and KRAS. 19 Of note, mLEF1 depended on β-Catenin to suppress proliferation, arguing that mLEF1 does not simply function as a dominant negative factor.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

SNAIL1 employs β‐Catenin‐LEF1 complexes to control colorectal cancer cell invasion and proliferation

Freihen

Rönsch

Mastroianni

et al. 2019

Intl Journal of Cancer

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The transcription factor SNAIL1 is a master regulator of epithelial‐to‐mesenchymal transition (EMT), a process entailing massive gene expression changes. To better understand SNAIL1‐induced transcriptional reprogramming we performed time‐resolved transcriptome analysis upon conditional SNAIL1 expression in colorectal cancer cells. Gene set variation analyses indicated that SNAIL1 strongly affected features related to cell cycle and Wnt/β‐Catenin signalling. This correlated with upregulation of LEF1, a nuclear binding partner of β‐Catenin. Likewise, transcriptomes of cell lines and colorectal cancers, including poor‐prognosis mesenchymal tumours, exhibit positively correlated SNAI1 and LEF1 expression, and elevated LEF1 levels parallel increased patient mortality. To delineate the functional contribution of LEF1 to SNAIL1‐induced EMT, we used the CRISPR/Cas9 system to knock‐out LEF1 in colorectal cancer cells, and to engineer cells that express LEF1 mutants unable to interact with β‐Catenin. Both complete LEF1‐deficiency and prevention of the β‐Catenin‐LEF1 interaction impaired the ability of SNAIL1 to elicit expression of an alternative set of Wnt/β‐catenin targets, and to promote cancer cell invasion. Conversely, overexpression of wildtype, but not of mutant LEF1, stimulated alternative Wnt/β‐Catenin target gene expression, and caused cell‐cycle arrest. Moreover, like SNAIL1, LEF1 retarded tumour growth in xenotransplantations. Thus, LEF1 phenocopies SNAIL1 with respect to several critical aspects of EMT. Indeed, comparative transcriptomics suggested that 35% of SNAIL1‐induced transcriptional changes are attributable to LEF1. However, LEF1 did not autonomously induce EMT. Rather, LEF1 appears to be a strictly β‐Catenin‐dependent downstream effector of SNAIL1. Apparently, SNAIL1 employs β‐Catenin‐LEF1 complexes to redirect Wnt/β‐Catenin pathway activity towards pro‐invasive and anti‐proliferative gene expression.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

SNAIL1 employs β‐Catenin‐LEF1 complexes to control colorectal cancer cell invasion and proliferation

Freihen

Rönsch

Mastroianni

et al. 2019

Intl Journal of Cancer

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“…However, in extreme diabetes mouse models with b-cell depletion, regeneration of insulin-producing cells has been shown to be controlled by TGFb signaling (79), whereas acute b-cell depletion by streptozotocin triggers the repopulation of b-cell mass from a rare population of Vim + MafB + cells (80). Given that EMT is a multi-stage process (81,82), one possibility is that the EMT process we report here represents a snap shot of an intermediary stage of a long-term regenerative process aimed at restoring b-cell mass.…”

Section: Smarca4/brg1 Is a Target Of Mir-7 In B-cellsmentioning

confidence: 99%

β-cell dedifferentiation is associated with epithelial-mesenchymal transition triggered by miR-7-mediated repression of mSwi/Snf complex

Mak

Ohlen

Wang

et al. 2019

Preprint

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b-cell dedifferentiation has been revealed as a pathological mechanism underlying pancreatic dysfunction in diabetes. However, little is known on the genetic and epigenetic changes linked with the dedifferentiation of b-cells. We now report that b-cell dedifferentiation is associated with epithelial to mesenchymal transition (EMT) triggered by miR-7-mediated repression of Smarca4/Brg1 expression, a catalytic subunit of the mSwi/Snf chromatin remodeling complexes essential for b-cell transcription factors (b-TFs) activity. miR-7-mediated repression of Brg1 expression in diabetes causes an overall compaction of chromatin structure preventing b-TFs from accessing and transactivating genes maintaining the functional and epithelial identity of b-cells. Concomitantly, loss of b-cell identity impairs the ability of b-TFs Pdx1, Nkx6-1, Neurod1 to repress non-b-cell genes enriched selectively in mesenchymal cells leading to EMT, change in islet microenvironment, and fibrosis. Remarkably, anti-EMT agents normalized glucose tolerance of diabetic mice, thus revealing mesenchymal reprogramming of b-cells as a novel therapeutic target in diabetes. This study sheds light on the genetic signature of dedifferentiated b-cells and highlights how loss of mSwi/Snf activity in diabetes initiating a step-wise remodeling of epigenetic landscapes of b-cells leading to the induction of an EMT process reminiscent of a response to tissue injury. specific miR-7 overexpressing mouse model (Tg7) which develops early-onset diabetes due to b-cell dedifferentiation (32). Conversely, how elevated miR-7 levels in diabetes impair b-cell identity remains unclear. By profiling gene expression and open chromatin regions of Tg7 islets, we now report that loss of b-cell identity triggers an islet injury response characterized by an epithelial to mesenchymal transition (EMT) process in both mouse and humans. Elevated miR-7 levels trigger the dedifferentiation of mature b-cells through the repression of Brg1/Smarca4, a catalytic subunit of mSwi/Snf chromatin remodelling complexes required for the transactivation lineagespecific and epithelial genes by b-cell transcription factors (b-TF) function. Our findings highlight how dysregulation miRNA networks can compromise the functional and epithelial identity of b-cells and trigger an EMT-like reprogramming process with therapeutic relevance in diabetes. RESULTS Loss of b-cells identity impairs islet connectivity in Tg7 miceGenetic overexpression of miR-7 in b-cells results in diabetes from 4 weeks of age and is associated with decreased expression of mature b-cell differentiation markers, most notably INS1/2 and b-TFs genes ( Supplementary Figure 1). How dedifferentiation affects Ca 2+ dynamics and long-range b-cell:b-cell connectivity in diabetes remains unclear. To this end, we monitored intracellular free Ca 2+ dynamics in intact islets in response to elevated concentrations of glucose using a trappable intracellular Ca 2+ dye and multicellular imaging.Ca 2+ dynamics in response to 17 mM glucose were almost...

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“…EMT is triggered by a genetic phenotype shift from epithelial-like to mesenchymal-like in response to pleiotropic signal; cells acquire the migratory and invasive properties by modifying adhesion molecules [3][4][5]. During this process, EMT specific transcription factors (EMT-TFs), in company with other regulatory factors like histone modifier and non-coding RNA, modify the gene expression through different states along EMT [6][7][8][9][10][11]. With the transcriptional activation of EMT-TFs, the expression of adherent junction components and tight junction components are negative-regulated, followed by the alteration in cadherin intermediate filament composition and cellular adhesion status [1, 3,8,9].…”

Section: Introductionmentioning

confidence: 99%

(20S)G-Rh2 Inhibits NF-κB Regulated Epithelial-Mesenchymal Transition by Targeting Annexin A2

Wang

et al. 2020

Biomolecules

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(1) Background: Epithelial-mesenchymal transition (EMT) is an essential step for cancer metastasis; targeting EMT is an important path for cancer treatment and drug development. NF-κB, an important transcription factor, has been shown to be responsible for cancer metastasis by enhancing the EMT process. Our previous studies showed that (20S)Ginsenoside Rh2 (G-Rh2) inhibits NF-κB activity by targeting Anxa2, but it is still not known whether this targeted inhibition of NF-κB can inhibit the EMT process. (2) Methods: In vivo (20S)G-Rh2-Anxa2 interaction was assessed by cellular thermal shift assay. Protein interaction was determined by immuno-precipitation analysis. NF-κB activity was determined by dual luciferase reporter assay. Gene expression was determined by RT-PCR and immuno-blot. EMT was evaluated by wound healing and Transwell assay and EMT regulating gene expression. (3) Results: Anxa2 interacted with the NF-κB p50 subunit, promoted NF-κB activation, then accelerated mesenchymal-like gene expression and enhanced cell motility; all these cellular processes were inhibited by (20S)G-Rh2. In contrast, these (20S)G-Rh2 effect were completely eliminated by overexpression of Anxa2-K301A, an (20S)G-Rh2-binding-deficient mutant of Anxa2. (4) Conclusion: (20S)G-Rh2 inhibited NF-κB activation and related EMT by targeting Anxa2 in MDA-MB-231 cells.

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A Hierarchical Regulatory Landscape during the Multiple Stages of EMT

Cited by 68 publications

References 39 publications

SNAIL1 employs β‐Catenin‐LEF1 complexes to control colorectal cancer cell invasion and proliferation

SNAIL1 employs β‐Catenin‐LEF1 complexes to control colorectal cancer cell invasion and proliferation

β-cell dedifferentiation is associated with epithelial-mesenchymal transition triggered by miR-7-mediated repression of mSwi/Snf complex

(20S)G-Rh2 Inhibits NF-κB Regulated Epithelial-Mesenchymal Transition by Targeting Annexin A2

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