Atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 controls the core epithelial-to-mesenchymal transition-inducing transcription factors

Epithelial to mesenchymal transition is an essential step in advanced cancer development. Many master transcription factors shift their expression to drive this process, while noncoding RNAs families like miR-200 are found to restrict it. In this study we investigated how the tumor suppressor miR-204 and several transcription factors modulate main markers of mesenchymal transformation like E- and N-cadherin, SLUG, VEGF, and SOX-9 in prostate cancer cell line model (LNCaP, PC3, VCaP, and NCI-H660). We found that SLUG, E-cadherin, and N-cadherin are differentially modulated by miR-204, using miR-204 specific mimics and inhibitors and siRNA gene silencing (RUNX2, ETS-1, and cMYB). The genome perturbation associated TMPRSS2-ERG fusion coincided with shift from tumor-suppressor to tumor-promoting activity of this miRNA. The ability of miR-204 to suppress cancer cell viability and migration was lost in the fusion harboring cell lines. We found differential E-cadherin splicing corroborating to miR-204 modulatory effects. RUNX2, ETS1, and cMYB are involved in the regulation of E-cadherin, N-cadherin, and VEGFA expression. RUNX2 knockdown results in SOX9 downregulation, while ETS1 and cMYB silencing result in SOX9 upregulation in VCaP cells. Their expression was found to be also methylation dependent. Our study provides means for understanding cancer heterogeneity in regard to adapted therapeutic approaches development.

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Posterior polymorphous corneal dystrophy – a disease caused by dysregulation of transcription factors involved in epithelial‐to‐mesenchymal transition

Acta Ophthalmologica ◽

10.1111/aos.13972_268 ◽

2018 ◽

Vol 96 (S261) ◽

pp. 73-74

Keyword(s):

Transcription Factors ◽

Epithelial To Mesenchymal Transition ◽

Corneal Dystrophy ◽

Mesenchymal Transition ◽

Posterior Polymorphous Corneal Dystrophy

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EMT Regulation by Autophagy: A New Perspective in Glioblastoma Biology

Cancers ◽

10.3390/cancers11030312 ◽

2019 ◽

Vol 11 (3) ◽

pp. 312 ◽

Cited By ~ 30

Author(s):

Barbara Colella ◽

Fiorella Faienza ◽

Sabrina Di Bartolomeo

Keyword(s):

Transcription Factors ◽

Tumor Cells ◽

Tissue Repair ◽

Epithelial To Mesenchymal Transition ◽

Signalling Pathways ◽

Migration And Invasion ◽

Cell Resistance ◽

Mesenchymal Phenotype ◽

Mesenchymal Transition ◽

New Perspective

Epithelial-to-mesenchymal transition (EMT) and its reverse process MET naturally occur during development and in tissue repair in vertebrates. EMT is also recognized as the crucial event by which cancer cells acquire an invasive phenotype through the activation of specific transcription factors and signalling pathways. Even though glial cells have a mesenchymal phenotype, an EMT-like process tends to exacerbate it during gliomagenesis and progression to more aggressive stages of the disease. Autophagy is an evolutionary conserved degradative process that cells use in order to maintain a proper homeostasis, and defects in autophagy have been associated to several pathologies including cancer. Besides modulating cell resistance or sensitivity to therapy, autophagy also affects the migration and invasion capabilities of tumor cells. Despite this evidence, few papers are present in literature about the involvement of autophagy in EMT-like processes in glioblastoma (GBM) so far. This review summarizes the current understanding of the interplay between autophagy and EMT in cancer, with special regard to GBM model. As the invasive behaviour is a hallmark of GBM aggressiveness, defining a new link between autophagy and EMT can open a novel scenario for targeting these processes in future therapeutical approaches.

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Epithelial to Mesenchymal Transition: A Mechanism that Fuels Cancer Radio/Chemoresistance

Cells ◽

10.3390/cells9020428 ◽

2020 ◽

Vol 9 (2) ◽

pp. 428 ◽

Cited By ~ 12

Author(s):

József Dudás ◽

Andrea Ladányi ◽

Julia Ingruber ◽

Teresa Bernadette Steinbichler ◽

Herbert Riechelmann

Keyword(s):

T Cells ◽

Transcription Factors ◽

Tumor Cells ◽

Epithelial To Mesenchymal Transition ◽

Protein Translation ◽

Therapy Resistance ◽

Mesenchymal Transition ◽

Rna Molecules ◽

Tumor Microenvironments ◽

Micro Rnas

Epithelial to mesenchymal transition (EMT) contributes to tumor progression, cancer cell invasion, and therapy resistance. EMT is regulated by transcription factors such as the protein products of the SNAI gene family, which inhibits the expression of epithelial genes. Several signaling pathways, such as TGF-beta1, IL-6, Akt, and Erk1/2, trigger EMT responses. Besides regulatory transcription factors, RNA molecules without protein translation, micro RNAs, and long non-coding RNAs also assist in the initialization of the EMT gene cluster. A challenging novel aspect of EMT research is the investigation of the interplay between tumor microenvironments and EMT. Several microenvironmental factors, including fibroblasts and myofibroblasts, as well as inflammatory, immune, and endothelial cells, induce EMT in tumor cells. EMT tumor cells change their adverse microenvironment into a tumor friendly neighborhood, loaded with stromal regulatory T cells, exhausted CD8+ T cells, and M2 (protumor) macrophages. Several EMT inhibitory mechanisms are instrumental in reversing EMT or targeting EMT cells. Currently, these mechanisms are also significant for clinical use.

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Synergistic action of master transcription factors controls epithelial-to-mesenchymal transition

Nucleic Acids Research ◽

10.1093/nar/gkw126 ◽

2016 ◽

Vol 44 (6) ◽

pp. 2514-2527 ◽

Cited By ~ 54

Author(s):

Hongyuan Chang ◽

Yuwei Liu ◽

Mengzhu Xue ◽

Haiyue Liu ◽

Shaowei Du ◽

...

Keyword(s):

Transcription Factors ◽

Epithelial To Mesenchymal Transition ◽

Synergistic Action ◽

Mesenchymal Transition

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Significance of epithelial-to-mesenchymal transition inducing transcription factors in predicting distance metastasis and survival in patients with colorectal cancer: A systematic review and meta-analysis

Journal of Research in Medical Sciences ◽

10.4103/jrms.jrms_174_19 ◽

2020 ◽

Vol 25 (1) ◽

pp. 60

Author(s):

Naghmeh Ahmadiankia ◽

Ahmad Khosravi

Keyword(s):

Colorectal Cancer ◽

Systematic Review ◽

Transcription Factors ◽

Epithelial To Mesenchymal Transition ◽

Meta Analysis ◽

Mesenchymal Transition

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Transcriptomic responses to hypoxia in endometrial and decidual stromal cells

10.1101/2019.12.21.885657 ◽

2019 ◽

Author(s):

Kalle T. Rytkönen ◽

Taija Heinosalo ◽

Mehrad Mahmoudian ◽

Xinghong Ma ◽

Antti Perheentupa ◽

...

Keyword(s):

Transcription Factors ◽

Stromal Cells ◽

Epithelial Mesenchymal Transition ◽

Cell Types ◽

Core Gene ◽

Stromal Fibroblasts ◽

Mesenchymal Transition ◽

The Core ◽

Transcriptomic Responses ◽

Upregulated Genes

AbstractHuman reproductive success depends on a properly decidualized uterine endometrium that allows implantation and the formation of the placenta. At the core of the decidualization process are endometrial stromal fibroblasts (ESF) that differentiate to decidual stromal cells (DSC). As variations in oxygen levels are functionally relevant in endometrium both upon menstruation and during placentation, we assessed the transcriptomic responses to hypoxia in ESF and DSC. In both cell types hypoxia upregulated genes in classical hypoxia pathways such as glycolysis and the epithelial mesenchymal transition. In DSC hypoxia restored an ESF like transcriptional state for a subset of transcription factors that are known targets of the progesterone receptor, suggesting that hypoxia partially interferes with progesterone signaling. In both cell types hypoxia modified transcription of several inflammatory transcription factors that are known regulators of decidualization, including decreased transcription of STATs and increased transcription of CEBPs. We observed that hypoxia upregulated genes had a significant overlap with genes previously detected to be upregulated in endometriotic stromal cells. Promoter analysis of the genes in this overlap suggested the hypoxia upregulated Jun/Fos and CEBP transcription factors as potential drivers of endometriosis-associated transcription. Using immunohistochemistry we observed increased expression of JUND and CEBPD in endometriosis lesions compared to healthy endometria. Overall the findings suggest that hypoxic stress establishes distinct transcriptional states in ESF and DSC, and that hypoxia influences the expression of genes that contribute to the core gene regulation of endometriotic stromal cells.

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