scholarly journals Distinct Cytosine Modification Profiles Define Epithelial-to-Mesenchymal Cell-State Transitions

2021 ◽  
Author(s):  
Min Kyung Lee ◽  
Meredith S. Brown ◽  
Owen Wilkins ◽  
Diwakar R. Pattabiraman ◽  
Brock C. Christensen
Keyword(s):  
Gene Expression ◽  
Cytosine Methylation ◽  
Epithelial To Mesenchymal Transition ◽  
Mesenchymal Cell ◽  
State Transitions ◽  
Open Chromatin ◽  
Intermediate Cell ◽  
Mesenchymal Transition ◽  
Accessible Chromatin ◽  
Cytosine Modification

Abstract Background: Epithelial-to-mesenchymal transition (EMT) is an early step in the invasion-metastasis cascade, involving progression through a number of cell intermediate states. Due to challenges with isolating intermediate cell states in EMT, genome-wide cytosine modification mechanisms that define transition through EMT states are not completely understood. We measured multiple DNA cytosine methylation modification marks, complemented with chromatin accessibility and gene expression, across clonal populations residing in specific EMT states. Results: Clones exhibiting intermediate EMT phenotypes demonstrated increased global 5-hydroxymethylcytosine (5hmC), decreased 5-methylcytosine (5mC), and more accesible chromatin. Open chromatin regions containing CpG loci with abundant 5hmC were enriched in motifs of key EMT transcription factors, ZEB1 and Snail. The magnitude of altered gene expression in intermediate cell states was higher for genes both with increased gene promoter 5hmC and differentially accessible chromatin compared with genes that exhibited differentially accessible chromatin alone, implicating functional epigenetic duality in regulation of EMT.Conclusion: Our results indicate the importance of both distinct and shared epigenetic profiles at the cytosine and chromatin level associated with EMT processes that contribute to gene regulation and which may be targeted to prevent the progression of EMT.

scholarly journals C-terminal domain small phosphatase-like 2 promotes epithelial-to-mesenchymal transition via Snail dephosphorylation and stabilization

Open Biology ◽  
2018 ◽  
Vol 8 (4) ◽  
pp. 170274 ◽  
Author(s):  
Yulan Zhao ◽  
Jinquan Liu ◽  
Fenfang Chen ◽  
Xin-Hua Feng
Keyword(s):  
Gene Expression ◽  
Epithelial Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Mammary Epithelial Cells ◽  
Critical Role ◽  
Mesenchymal Cell ◽  
Cellular Reprogramming ◽  
Mammary Epithelial ◽  
Mesenchymal Transition ◽  
Proteasome Degradation

The epithelial-to-mesenchymal transition (EMT) is a cellular reprogramming process converting epithelial cells into mesenchymal cell morphology. Snail is a critical regulator of EMT by both suppressing epithelial gene expression and promoting mesenchymal gene expression. Expression and activity of Snail are tightly controlled at transcriptional and post-translational levels. It has previously been reported that Snail undergoes phosphorylation and ubiquitin-dependent proteasome degradation. Here, we report nuclear phosphatase SCP4/CTDSPL2 acts as a novel Snail phosphatase. SCP4 physically interacts with and directly dephosphorylates Snail. SCP4-mediated dephosphorylation of Snail suppresses the ubiquitin-dependent proteasome degradation of Snail and consequently enhances TGFβ-induced EMT. The knockdown of SCP4 in MCF10A mammary epithelial cells leads to attenuated cell migration. Collectively, our finding demonstrates that SCP4 plays a critical role in EMT through Snail dephosphorylation and stabilization.

scholarly journals Modulation of Epithelial to Mesenchymal Transition Signaling Pathways by Olea Europaea and Its Active Compounds

2019 ◽  
Vol 20 (14) ◽  
pp. 3492 ◽  
Author(s):  
Rabiatul Adawiyah Razali ◽  
Yogeswaran Lokanathan ◽  
Muhammad Dain Yazid ◽  
Ayu Suraya Ansari ◽  
Aminuddin Bin Saim ◽  
...  
Keyword(s):  
Olea Europaea ◽  
Epithelial To Mesenchymal Transition ◽  
Epithelial Mesenchymal Transition ◽  
Healing Process ◽  
Mesenchymal Cell ◽  
Cell Phenotype ◽  
Wound Healing Process ◽  
Active Compounds ◽  
Mesenchymal Transition ◽  
Olea Europaéa

Epithelial-mesenchymal transition (EMT) is a significant dynamic process that causes changes in the phenotype of epithelial cells, changing them from their original phenotype to the mesenchymal cell phenotype. This event can be observed during wound healing process, fibrosis and cancer. EMT-related diseases are usually caused by inflammation that eventually leads to tissue remodeling in the damaged tissue. Prolonged inflammation causes long-term EMT activation that can lead to tissue fibrosis or cancer. Due to activation of EMT by its signaling pathway, therapeutic approaches that modulate that pathway should be explored. Olea europaea (OE) is well-known for its anti-inflammatory effects and abundant beneficial active compounds. These properties are presumed to modulate EMT events. This article reviews recent evidence of the effects of OE and its active compounds on EMT events and EMT-related diseases. Following evidence from the literature, it was shown that OE could modulate TGFβ/SMAD, AKT, ERK, and Wnt/β-catenin pathways in EMT due to a potent active compound that is present therein.

Detection of Synergistic Combinatorial Perturbations by a Bifurcation-Based Approach

2021 ◽  
Vol 31 (12) ◽  
pp. 2150175
Author(s):  
Min Luo ◽  
Dasong Huang ◽  
Jianfeng Jiao ◽  
Ruiqi Wang
Keyword(s):  
Gene Expression ◽  
Rational Design ◽  
Epithelial To Mesenchymal Transition ◽  
Regulation Of Gene Expression ◽  
Drug Combinations ◽  
Bifurcation Curve ◽  
Combinatorial Regulation ◽  
Mesenchymal Transition ◽  
Combinatorial Control ◽  
Two Parameters

Drug combination has become an attractive strategy against complex diseases, despite the challenges in handling a large number of possible combinations among candidate drugs. How to detect effective drug combinations and determine the dosage of each drug in the combination is still a challenging task. When regarding a drug as a perturbation, we propose a bifurcation-based approach to detect synergistic combinatorial perturbations. In the approach, parameters of a dynamical system are divided into two groups according to their responses to perturbations. By combining two parameters chosen from two groups, three types of combinations can be obtained. Synergism for different perturbation combinations can be detected by relative positions of the bifurcation curve and the isobole. The bifurcation-based approach can be used not only to detect combinatorial perturbations but also to determine their perturbation quantities. To demonstrate the effectiveness of the approach, we apply it to the epithelial-to-mesenchymal transition (EMT) network. The approach has implications for the rational design of drug combinations and other combinatorial control, e.g. combinatorial regulation of gene expression.

scholarly journals Growing Evidence of Exosomal MicroRNA-Related Metastasis of Hepatocellular Carcinoma

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Wenbing Sun ◽  
Shuqi Fu ◽  
Size Wu ◽  
Rong Tu
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Cause Of Death ◽  
Distant Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Regulate Gene Expression ◽  
Mesenchymal Transition ◽  
Exosomal Microrna ◽  
Regulate Gene

Metastasis is the prominent cause of death in patients with hepatocellular carcinoma (HCC); however, the mechanisms behind HCC metastasis are not well understood. MicroRNAs (miRs) can regulate gene expression and affect HCC metastasis. Exosomes can transport miRs and other cargoes to and from different cells, thus being associated with tumour-distant metastasis. Exosomal miRs involve different processes of HCC metastasis through their functional effects, such as their induction of epithelial-to-mesenchymal transition, angiogenesis, and distant niche. In this review, data from the literature were analysed and summarised, with a focus on the evidence extraction of exosomal miRs in HCC metastasis with the purpose of increasing the understanding of the mechanisms behind HCC metastasis and acquiring implications for application.

scholarly journals Cathepsin B Is Upregulated and Mediates ECM Degradation in Colon Adenocarcinoma HT29 Cells Overexpressing Snail

Cells ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 203 ◽  
Author(s):  
Jakub Kryczka ◽  
Izabela Papiewska-Pajak ◽  
M. Anna Kowalska ◽  
Joanna Boncela
Keyword(s):  
Cathepsin B ◽  
Epithelial To Mesenchymal Transition ◽  
Early Stage ◽  
Tumor Development ◽  
Colon Adenocarcinoma ◽  
Mesenchymal Cell ◽  
Tissue Samples ◽  
Mesenchymal Transition ◽  
Colon And Rectum ◽  
Phenotypic Shift

During tumor development and ongoing metastasis the acquisition of mesenchymal cell traits by epithelial carcinoma cells is achieved through a programmed phenotypic shift called the epithelial-to-mesenchymal transition, EMT. EMT contributes to increased cancer cell motility and invasiveness mainly through invadosomes, the adhesion structures that accompany the mesenchymal migration. The invadosomes and their associated proteases restrict protease activity to areas of the cell in direct contact with the ECM, thus precisely controlling cell invasion. Our data prove that Snail-overexpressing HT-29 cells that imitate the phenotype of colon cancer cells in the early stage of the EMT showed an increase in the expression and pericellular activity of cathepsin B. It appears that the pericellular localization of cathepsin B, also observed in colon and rectum adenocarcinoma tissue samples, plays a key role in its function.

Decline in serum soluble E-cadherin and low baseline matrix metalloproteinase-9 are associated with response to combination celecoxib and erlotinib therapy in advanced non-small cell lung cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7640-7640
Author(s):  
K. L. Reckamp ◽  
B. K. Gardner ◽  
R. A. Figlin ◽  
D. Elashoff ◽  
K. Krysan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Combination Therapy ◽  
Matrix Metalloproteinase ◽  
Epithelial To Mesenchymal Transition ◽  
Advanced Nsclc ◽  
Mesenchymal Transition ◽  
Best Response ◽  
Cox 2 ◽  
E Cadherin

7640 Background: Cyclooxygenase-2 (COX-2) overexpression may mediate resistance to EGFR TK inhibition through prostaglandin E2 (PGE2)-dependent promotion of epithelial to mesenchymal transition (EMT). Thomson, et al. reported that the suppression of epithelial markers such as E-cadherin led to resistance to erlotinib (Cancer Res 2005;65:9455). In addition, PGE2 downregulates E-cadherin expression by upregulating transcriptional repressors including ZEB1 and Snail, as described by Dohadwala et al (Cancer Res 2006;66:5338). These findings suggest that COX-2 inhibition may enhance the efficacy of EGFR TKI therapy in NSCLC. Methods: A phase I, dose escalation trial to was performed investigating the combination of celecoxib and erlotinib in pts with advanced NSCLC. Soluble E-cadherin (sEC) was evaluated by ELISA in pt serum at baseline and weeks 4 and 8 of treatment. Other markers of COX-2 gene expression were evaluated by ELISA, including matrix metalloproteinase (MMP)-9, MMP-2 and tissue inhibitor of MMP (TIMP1). Results: 22 pts were enrolled and 21 were evaluable for the determination of the optimal dose, toxicity assessment and response (reported in Clin Cancer Res 2006;12:3381). Here we report serum sEC and MMP-9 levels, which were analyzed according to best response (PR, SD or PD) in 21 pts. SEC was analyzed according to best response (PR, SD or PD). We found a significant decrease in sEC between baseline and week 8 in pts with PR when compared to those with SD or PD (p = 0.021). In pts who responded to the combination therapy, baseline MMP-9 was significantly lower compared to non-responders (p = 0.006). Conclusions: SEC, MMP-9 and other downstream markers of COX-2 gene expression may be useful for assessing response to combination celecoxib and erlotinib in pts with advanced NSCLC. A randomized Phase II trial is planned comparing erlotinib and celecoxib with erlotinib plus placebo in advanced NSCLC, to evaluate the efficacy of this combination therapy and to assess these and other biomarkers in both serum and tumor tissue. Supported by ASCO Young Investigator Award, UCLA Lung Cancer SPORE NCI P50 CA 90388 and GLAVAHS Career Development Award. No significant financial relationships to disclose.

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