scholarly journals Post-translational modifications of EMT transcriptional factors in cancer metastasis

2016 ◽  
Vol 11 (1) ◽  
pp. 237-243 ◽  
Author(s):  
Rui Chang ◽  
Peng Zhang ◽  
Jiacong You
Keyword(s):  
Protein Modification ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Transcriptional Factors ◽  
Protein Stabilization ◽  
Biological Behavior ◽  
Post Translational Modifications ◽  
Mesenchymal Transition ◽  
Substrate Proteins ◽  
E Cadherin

AbstractMetastasis is an important reason for death of cancer patients which characterized as the formation of secondary cancers at distant sites. Epithelial– mesenchymal transition (EMT) is a dynamic process that appear to facilitate tumor metastasis in various cancers by switching epithelial cells into mesenchymal properties. Although previous investigation suggested a key role of EMT transcriptional factors in suppression of E-cadherin, the association of these factors with other cellular regulators in cancer metastasis need to be fully elucidated. Post-translational modifications (PTMs), such as acetylation and phosphorylation, have emerged as an important mechanism to modulate biological behavior of substrate proteins. In this review, we summarized protein modification and subsequent function changes of Snail, Twist and ZEB, as well as their influence on tumor progression. Acetylation of EMT transcriptional factors usually cause nuclear localization and/or protein stabilization thus contribute to E-cadherin repression. Besides, Twist and ZEB were phosphorylated by diverse kinases to promote metastasis in many cancers, while Snail was negatively regulated by phosphorylation to degradation. Then, the potential of therapy for metastasis by targeting PTMs-involved regulation of EMT transcriptional factors were discussed.

scholarly journals Roles of the Phosphorylation of Transcriptional Factors in Epithelial-Mesenchymal Transition

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Rong Xu ◽  
Jae-Yeon Won ◽  
Chang-Hyeon Kim ◽  
Da-Eun Kim ◽  
Hyungshin Yim
Keyword(s):  
Transcription Factors ◽  
Posttranslational Modifications ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Epithelial Mesenchymal Transition ◽  
Transcriptional Factors ◽  
Mesenchymal Transition ◽  
Protein Protein Interaction ◽  
Expression Of Genes ◽  
E Cadherin

Epithelial-to-mesenchymal transition (EMT) is the first step in the development of the invasive and migratory properties of cancer metastasis. Since the transcriptional reprogramming of a number of genes occurs in EMT, the regulation of EMT transcription factors has been intensively investigated. EMT transcriptional factors are commonly classified by the direct or indirect repression of E-cadherin because one of hallmarks of EMT is the loss of E-cadherin. This facilitates the expression of genes for EMT, tumor invasion, and metastasis. The posttranslational modification of EMT transcriptional factors, such as Snail and Slug, directly regulates their functions, including their stability, nuclear localization, protein-protein interaction, and ubiquitination for the promotion or termination of EMT at the specific points. Here, we discuss how posttranslational modifications regulate gene expression in a dynamic and reversible manner by modifying upstream signaling pathways, focusing in particular on the posttranslational modifications of Snail, Slug, ZEB1, ZEB2, and TWIST1. This review demonstrates that EMT transcription factors regulate metastasis through their posttranslational modifications and that the flexibility and reversibility of EMT can be modified by phosphorylation.

scholarly journals Inhibitor of DNA-Binding Protein 4 Suppresses Cancer Metastasis through the Regulation of Epithelial Mesenchymal Transition in Lung Adenocarcinoma

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 2021 ◽  
Author(s):  
Chi-Chung Wang ◽  
Yuan-Ling Hsu ◽  
Chi-Jen Chang ◽  
Chia-Jen Wang ◽  
Tzu-Hung Hsiao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Binding ◽  
Lung Adenocarcinoma ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Inhibitor Of Dna Binding ◽  
E Cadherin

Metastasis is a predominant cause of cancer death and the major challenge in treating lung adenocarcinoma (LADC). Therefore, exploring new metastasis-related genes and their action mechanisms may provide new insights for developing a new combative approach to treat lung cancer. Previously, our research team discovered that the expression of the inhibitor of DNA binding 4 (Id4) was inversely related to cell invasiveness in LADC cells by cDNA microarray screening. However, the functional role of Id4 and its mechanism of action in lung cancer metastasis remain unclear. In this study, we report that the expression of Id4 could attenuate cell migration and invasion in vitro and cancer metastasis in vivo. Detailed analyses indicated that Id4 could promote E-cadherin expression through the binding of Slug, cause the occurrence of mesenchymal-epithelial transition (MET), and inhibit cancer metastasis. Moreover, the examination of the gene expression database (GSE31210) also revealed that high-level expression of Id4/E-cadherin and low-level expression of Slug were associated with a better clinical outcome in LADC patients. In summary, Id4 may act as a metastatic suppressor, which could not only be used as an independent predictor but also serve as a potential therapeutic for LADC treatment.

scholarly journals NRF2 activates a partial epithelial-mesenchymal transition and is maximally present in a hybrid epithelial/mesenchymal phenotype

2019 ◽  
Vol 11 (6) ◽  
pp. 251-263 ◽  
Author(s):  
Federico Bocci ◽  
Satyendra C Tripathi ◽  
Samuel A Vilchez Mercedes ◽  
Jason T George ◽  
Julian P Casabar ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Therapy Resistance ◽  
Collective Cell Migration ◽  
Mesenchymal Transition ◽  
Regulatory Circuit ◽  
Clinical Records ◽  
E Cadherin

Abstract The epithelial-mesenchymal transition (EMT) is a key process implicated in cancer metastasis and therapy resistance. Recent studies have emphasized that cells can undergo partial EMT to attain a hybrid epithelial/mesenchymal (E/M) phenotype – a cornerstone of tumour aggressiveness and poor prognosis. These cells can have enhanced tumour-initiation potential as compared to purely epithelial or mesenchymal ones and can integrate the properties of cell-cell adhesion and motility that facilitates collective cell migration leading to clusters of circulating tumour cells (CTCs) – the prevalent mode of metastasis. Thus, identifying the molecular players that can enable cells to maintain a hybrid E/M phenotype is crucial to curb the metastatic load. Using an integrated computational-experimental approach, we show that the transcription factor NRF2 can prevent a complete EMT and instead stabilize a hybrid E/M phenotype. Knockdown of NRF2 in hybrid E/M non-small cell lung cancer cells H1975 and bladder cancer cells RT4 destabilized a hybrid E/M phenotype and compromised the ability to collectively migrate to close a wound in vitro. Notably, while NRF2 knockout simultaneously downregulated E-cadherin and ZEB-1, overexpression of NRF2 enriched for a hybrid E/M phenotype by simultaneously upregulating both E-cadherin and ZEB-1 in individual RT4 cells. Further, we predict that NRF2 is maximally expressed in hybrid E/M phenotype(s) and demonstrate that this biphasic dynamic arises from the interconnections among NRF2 and the EMT regulatory circuit. Finally, clinical records from multiple datasets suggest a correlation between a hybrid E/M phenotype, high levels of NRF2 and its targets and poor survival, further strengthening the emerging notion that hybrid E/M phenotype(s) may occupy the ‘metastatic sweet spot’.

scholarly journals BTBD7 Downregulates E-Cadherin and Promotes Epithelial-Mesenchymal Transition in Lung Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Jie Shu ◽  
Lin Wang ◽  
Fei Han ◽  
Yubin Chen ◽  
Shunjun Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Western Blotting ◽  
Nude Mice ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
A549 Cells ◽  
Migration Ability ◽  
Mesenchymal Transition ◽  
Qrt Pcr ◽  
E Cadherin

Metastasis is the leading cause of lung cancer-associated death. Downregulated expression of E-cadherin followed by epithelial-mesenchymal transition (EMT) is critical for metastasis initiation in lung cancer. BTBD7 plays essential roles in lung cancer metastasis, but the mechanisms remain unknown. This study aimed to investigate the relationship between BTBD7 and E-cadherin in lung cancer and explore the role of BTBD7 in EMT. Fresh lung cancer and paracancer tissue specimens were collected from 30 patients, and the expression of BTBD7, E-cadherin, N-cadherin, fibronectin, and vimentin was analyzed by qRT-PCR, western blotting, and immunohistochemistry. A549 and HBE cells were cultured and treated with TGF-β1 for 72 h to induce EMT. Western blotting and qRT-PCR were performed to evaluate the expression of BTBD7, E-cadherin, N-cadherin, fibronectin, and vimentin. Then, A549 cells were treated separately with the BTBD7-ENTER plasmid, BTBD7-siRNA, and paclitaxel. After TGF-β1-induced EMT, the abovementioned markers were analyzed by western blotting and qRT-PCR. Wound healing assays were applied to assess the migration ability of cells in different groups. For animal experiments, A549 cells transfected with the BTBD7-ENTER plasmid were transplanted into BALB/c nude mice. After 4 weeks, all nude mice were sacrificed, and tumor tissues were harvested for qRT-PCR, western blot, and immunohistochemical analyses of the abovementioned markers. All experimental results showed that the levels of BTBD7, N-cadherin, fibronectin, and vimentin were increased in lung cancer tissues and cells, while the E-cadherin level was decreased. Transfection experiments showed that BTBD7 inhibited E-cadherin expression and enhanced EMT. Moreover, the migration capacity of lung cancer cells was increased by the high level of BTBD7. We concluded that BTBD7 is highly expressed during lung cancer development and metastasis and can inhibit the expression of E-cadherin and promote EMT in lung cancer. BTBD7 may thus be a therapeutic target for lung cancer.

scholarly journals Expression of E-Cadherin in Epithelial Cancer Cells Increases Cell Motility and Directionality through the Localization of ZO-1 during Collective Cell Migration

2021 ◽  
Vol 8 (5) ◽  
pp. 65
Author(s):  
Song-Yi Park ◽  
Hwanseok Jang ◽  
Seon-Young Kim ◽  
Dasarang Kim ◽  
Yongdoo Park ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cell Motility ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Cell Contact ◽  
Collective Cell Migration ◽  
Collective Migration ◽  
Ags Cells ◽  
Mesenchymal Transition ◽  
E Cadherin

Collective cell migration of epithelial tumor cells is one of the important factors for elucidating cancer metastasis and developing novel drugs for cancer treatment. Especially, new roles of E-cadherin in cancer migration and metastasis, beyond the epithelial–mesenchymal transition, have recently been unveiled. Here, we quantitatively examined cell motility using micropatterned free edge migration model with E-cadherin re-expressing EC96 cells derived from adenocarcinoma gastric (AGS) cell line. EC96 cells showed increased migration features such as the expansion of cell islands and straightforward movement compared to AGS cells. The function of tight junction proteins known to E-cadherin expression were evaluated for cell migration by knockdown using sh-RNA. Cell migration and straight movement of EC96 cells were reduced by knockdown of ZO-1 and claudin-7, to a lesser degree. Analysis of the migratory activity of boundary cells and inner cells shows that EC96 cell migration was primarily conducted by boundary cells, similar to leader cells in collective migration. Immunofluorescence analysis showed that tight junctions (TJs) of EC96 cells might play important roles in intracellular communication among boundary cells. ZO-1 is localized to the base of protruding lamellipodia and cell contact sites at the rear of cells, indicating that ZO-1 might be important for the interaction between traction and tensile forces. Overall, dynamic regulation of E-cadherin expression and localization by interaction with ZO-1 protein is one of the targets for elucidating the mechanism of collective migration of cancer metastasis.

scholarly journals A Multiscale computational model of YAP signaling in epithelial fingering behaviour

2021 ◽  
Author(s):  
Naba Mukhtar ◽  
Leah Edelstein-Keshet ◽  
Eric N Cytrynbaum
Keyword(s):  
Wound Healing ◽  
Intracellular Signaling ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Model Simulation ◽  
Multiscale Model ◽  
Cellular Potts Model ◽  
Mesenchymal Transition ◽  
E Cadherin

In epithelial-mesenchymal transition (EMT), cells organized into sheets break away and become motile mesenchymal cells. EMT plays a crucial role in wound healing, embryonic development, and cancer metastasis. Intracellular signaling in response to mechanical, topographic, or chemical stimuli can promote EMT. We present a multiscale model for EMT downstream of the protein YAP, which suppresses the cell-cell adhesion protein E-cadherin and activates the GTPase Rac1 that enhances cell migration. We first propose an ODE model for YAP/Rac1/E-cadherin interactions. The model dynamics are bistable, accounting for motile loose cells as for adherent slower cells. We implement this model in a cellular Potts model simulation of 2D wound-healing using the open source platform Morpheus. We show that, under suitable stimuli (depicting topographic cues) the sheet exhibits finger-like projections and EMT. Morphological, as well as quantitative differences in YAP levels as well as cell speed across the sheet are consistent with preexisting experimental observations of epithelial sheets grown on topographic features in vitro. The simulation is also consistent with experiments that knockdown or over-express YAP, inhibit Rac1, or block E-cadherin.

scholarly journals E3 Ubiquitin Ligases in Breast Cancer Metastasis: A Systematic Review of Pathogenic Functions and Clinical Implications

2021 ◽  
Vol 11 ◽  
Author(s):  
Yingshuang Wang ◽  
Jiawen Dai ◽  
Youqin Zeng ◽  
Jinlin Guo ◽  
Jie Lan
Keyword(s):  
Breast Cancer ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Breast ◽  
Ubiquitin Ligases ◽  
Breast Cancer Metastasis ◽  
Biological Behavior ◽  
E3 Ubiquitin Ligases ◽  
Mesenchymal Transition ◽  
Protein Ubiquitination

Female breast cancer has become the most commonly occurring cancer worldwide. Although it has a good prognosis under early diagnosis and appropriate treatment, breast cancer metastasis drastically causes mortality. The process of metastasis, which includes cell epithelial–mesenchymal transition, invasion, migration, and colonization, is a multistep cascade of molecular events directed by gene mutations and altered protein expressions. Ubiquitin modification of proteins plays a common role in most of the biological processes. E3 ubiquitin ligase, the key regulator of protein ubiquitination, determines the fate of ubiquitinated proteins. E3 ubiquitin ligases target a broad spectrum of substrates. The aberrant functions of many E3 ubiquitin ligases can affect the biological behavior of cancer cells, including breast cancer metastasis. In this review, we provide an overview of these ligases, summarize the metastatic processes in which E3s are involved, and comprehensively describe the roles of E3 ubiquitin ligases. Furthermore, we classified E3 ubiquitin ligases based on their structure and analyzed them with the survival of breast cancer patients. Finally, we consider how our knowledge can be used for E3s’ potency in the therapeutic intervention or prognostic assessment of metastatic breast cancer.

scholarly journals Curcumin Inhibits the Migration and Invasion of Non-Small-Cell Lung Cancer Cells Through Radiation-Induced Suppression of Epithelial-Mesenchymal Transition and Soluble E-Cadherin Expression

2020 ◽  
Vol 19 ◽  
pp. 153303382094748
Author(s):  
Xinzhou Deng ◽  
Chunli Chen ◽  
Feng Wu ◽  
Li Qiu ◽  
Qing Ke ◽  
...  
Keyword(s):  
Cell Migration ◽  
A549 Cell ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Cell Migration And Invasion ◽  
Mmp9 Expression ◽  
Radiation Induced ◽  
E Cadherin

Radiotherapy has been reported to cause cancer metastasis. Thus, a new strategy for radiotherapy must be developed to avoid this side effect. A549 cells were exposed to radiation to induce an epithelial-mesenchymal transition (EMT) cell model. Real-time PCR and western blotting were used to detect mRNA and protein expression levels, and Transwell invasion and wound healing assays were used to detect cell migration and invasion. ELISA was used to detect soluble E-cadherin (sE-cad) secretion. siRNA was used to silence MMP9 expression. The results show that A549R cells exhibited an EMT phenotype with increased E-cadherin, N-cadherin, Snail, Slug, vimentin and Twist expression and decreased pan-keratin expression. sE-cad levels were increased in A549R cells and in the serum of NSCLC patients with distant metastasis. Exogenous sE-cad treatment and sE-cad overexpression promoted A549R and A549 cell migration and invasion. In contrast, blocking sE-cad attenuated A549 cell migration and invasion. Curcumin inhibited sE-cad expression and reversed EMT induced by radiation. Furthermore, curcumin suppressed sE-cad-enhanced A549 and A549R cell migration and invasion. Curcumin inhibited MMP9 expression, and silencing MMP9 suppressed sE-cad expression. Taken together, we found a nonclassic EMT phenomenon induced by radiation. Curcumin inhibits NSCLC migration and invasion by suppressing radiation-induced EMT and sE-cad expression by decreasing MMP9 expression.

scholarly journals Epigenetic Regulation and Post-Translational Modifications of SNAI1 in Cancer Metastasis

2021 ◽  
Vol 22 (20) ◽  
pp. 11062
Author(s):  
Bo Dong ◽  
Yadi Wu
Keyword(s):  
Cancer Progression ◽  
Epigenetic Regulation ◽  
Tumor Metastasis ◽  
Metabolic Regulation ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Post Translational Modifications ◽  
Mesenchymal Transition ◽  
Novel Therapeutic Strategies

SNAI1, a zinc finger transcription factor, not only acts as the master regulator of epithelial-mesenchymal transition (EMT) but also functions as a driver of cancer progression, including cell invasion, survival, immune regulation, stem cell properties, and metabolic regulation. The regulation of SNAI1 occurs at the transcriptional, translational, and predominant post-translational levels including phosphorylation, acetylation, and ubiquitination. Here, we discuss the regulation and role of SNAI1 in cancer metastasis, with a particular emphasis on epigenetic regulation and post-translational modifications. Understanding how signaling networks integrate with SNAI1 in cancer progression will shed new light on the mechanism of tumor metastasis and help develop novel therapeutic strategies against cancer metastasis.

scholarly journals TdIF1-LSD1 Axis Regulates Epithelial—Mesenchymal Transition and Metastasis via Histone Demethylation of E-Cadherin Promoter in Lung Cancer

2021 ◽  
Vol 23 (1) ◽  
pp. 250
Author(s):  
Qi Liu ◽  
Juan Xiong ◽  
Derong Xu ◽  
Nan Hao ◽  
Yujuan Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Promoter Region ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
The Cancer Genome Atlas ◽  
Migration And Invasion ◽  
Clinical Samples ◽  
Related Factors ◽  
Mesenchymal Transition ◽  
E Cadherin

We have previously found that TdT-interacting factor 1 (TdIF1) is a potential oncogene expressed in non-small cell lung cancer (NSCLC) and is associated with poor prognosis. However, its exact mechanism is still unclear. The lysine-specific demethylase 1 (LSD1) is a crucial mediator of the epithelial–mesenchymal transition (EMT), an important process triggered during cancer metastasis. Here, we confirm that TdIF1 is highly expressed in NSCLC and related to lymph node metastasis through The Cancer Genome Atlas (TCGA) analysis of clinical samples. Silencing TdIF1 can regulate the expression of EMT-related factors and impair the migration and invasion ability of cancer cells in vitro. An analysis of tumor xenografts in nude mice confirmed that silencing TdIF1 inhibits tumor growth. Furthermore, we determined the interaction between TdIF1 and LSD1 using immunoprecipitation. Chromatin immunoprecipitation (ChIP) revealed that TdIF1 was enriched in the E-cadherin promoter region. The knockdown of TdIF1 repressed the enrichment of LSD1 at the E-cadherin promoter region, thereby regulating the level of promoter histone methylation and modulating E-cadherin transcription activity, ultimately leading to changes in EMT factors and cancer cell migration and invasion ability. The LSD1 inhibitor and TdIF1 knockdown combination showed a synergistic effect in inhibiting the growth, migration, and invasion of NSCLC cells. Taken together, this is the first demonstration that TdIF1 regulates E-cadherin transcription by recruiting LSD1 to the promoter region, thereby promoting EMT and tumor metastasis and highlighting the potential of TdIF1 as a therapeutic target for NSCLC.

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