ETS1 is coexpressed with ZEB2 and mediates ZEB2‐induced epithelial‐mesenchymal transition in human tumors

Yalim-Camci, Irem; Balçık-Erçin, Pelin; Çetįn, Metin; Odabas, Gorkem; Tokay, Nurettin; Sayan, Emre; Yağcı, Tamer

doi:10.1002/mc.22994

Cited by 29 publications

(24 citation statements)

References 63 publications

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“…ETS1 is associated with poor prognosis and therapy resistance in most of the cancers [107][108][109][110]. ETS1 is required for ZEB2-induced EMT phenotype, where it regulates ZEB2-mediated expression of Twist and MMP-9 [111], and can function as a master regulator of TGF-β-associated EMT in the mesenchymal subtypes of head and neck squamous cell carcinoma (HNSCC) [112]. ETS1 has been shown to regulate cellular metabolism in ovarian cancer cells resulting in the up-regulation of key enzymes involved in glycolysis [113].…”

Section: Ets1mentioning

confidence: 99%

Transcription Factors in Cancer Development and Therapy

Vishnoi

Viswakarma

Rana

et al. 2020

Cancers

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Cancer is a multi-step process and requires constitutive expression/activation of transcription factors (TFs) for growth and survival. Many of the TFs reported so far are critical for carcinogenesis. These include pro-inflammatory TFs, hypoxia-inducible factors (HIFs), cell proliferation and epithelial–mesenchymal transition (EMT)-controlling TFs, pluripotency TFs upregulated in cancer stem-like cells, and the nuclear receptors (NRs). Some of those, including HIFs, Myc, ETS-1, and β-catenin, are multifunctional and may regulate multiple other TFs involved in various pro-oncogenic events, including proliferation, survival, metabolism, invasion, and metastasis. High expression of some TFs is also correlated with poor prognosis and chemoresistance, constituting a significant challenge in cancer treatment. Considering the pivotal role of TFs in cancer, there is an urgent need to develop strategies targeting them. Targeting TFs, in combination with other chemotherapeutics, could emerge as a better strategy to target cancer. So far, targeting NRs have shown promising results in improving survival. In this review, we provide a comprehensive overview of the TFs that play a central role in cancer progression, which could be potential therapeutic candidates for developing specific inhibitors. Here, we also discuss the efforts made to target some of those TFs, including NRs.

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Section: Ets1mentioning

confidence: 99%

Transcription Factors in Cancer Development and Therapy

Vishnoi

Viswakarma

Rana

et al. 2020

Cancers

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“…In hematopietic stem cells, for example, TWIST1 binds to the promoter of Gata2 and induces its transcription (Kulkeaw et al, 2017), while in nasopharyngeal carcinoma cells, GATA2 induces EMT by binding to the promoter of Twist1 and activating its expression (Wang et al, 2017b). Furthermore, ETS1 and ZEB2 activate each other's transcription (Katoh and Katoh, 2009;Yalim-Camci et al, 2019).…”

Section: Key Transcription Factors For Endothelial and Mesenchymal Idmentioning

confidence: 99%

A Computational Model of the Endothelial to Mesenchymal Transition

2020

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Endothelial cells (ECs) form the lining of lymph and blood vessels. Changes in tissue requirements or wounds may cause ECs to behave as tip or stalk cells. Alternatively, they may differentiate into mesenchymal cells (MCs). These processes are known as EC activation and endothelial-to-mesenchymal transition (EndMT), respectively. EndMT, Tip, and Stalk EC behaviors all require SNAI1, SNAI2, and Matrix metallopeptidase (MMP) function. However, only EndMT inhibits the expression of VE-cadherin, PECAM1, and VEGFR2, and also leads to EC detachment. Physiologically, EndMT is involved in heart valve development, while a defective EndMT regulation is involved in the physiopathology of cardiovascular malformations, congenital heart disease, systemic and organ fibrosis, pulmonary arterial hypertension, and atherosclerosis. Therefore, the control of EndMT has many promising potential applications in regenerative medicine. Despite the fact that many molecular components involved in EC activation and EndMT have been characterized, the system-level molecular mechanisms involved in this process have not been elucidated. Toward this end, hereby we present Boolean network model of the molecular involved in the regulation of EC activation and EndMT. The simulated dynamic behavior of our model reaches fixed and cyclic patterns of activation that correspond to the expected EC and MC cell types and behaviors, recovering most of the specific effects of simple gain and loss-of-function mutations as well as the conditions associated with the progression of several diseases. Therefore, our model constitutes a theoretical framework that can be used to generate hypotheses and guide experimental inquiry to comprehend the regulatory mechanisms behind EndMT. Our main findings include that both the extracellular microevironment and the pattern of molecular activity within the cell regulate EndMT. EndMT requires a lack of VEGFA and sufficient oxygen in the extracellular microenvironment as well as no FLI1 and GATA2 activity within the cell. Additionally Tip cells cannot undergo EndMT directly. Furthermore, the specific conditions that are sufficient to trigger EndMT depend on the specific pattern of molecular activation within the cell.

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“…We showed that ERN1 knockdown of glioma cells leads to a strong down-regulation of the expression of ZEB2 gene under glucose deprivation. Homeobox protein ZEB2 is functioning as an oncogene in human laryngeal squamous cell carcinoma and acts as an upstream positive regulator of ETS1 (ETS proto-oncogene 1) (Li et al 2019;Yalim-Camci et al 2019). Furthermore, transcription factor ETS1 is coexpressed with ZEB2 and mediates ZEB2-induced epithelial-mesenchymal transition in human tumors (Yalim-Camci et al 2019).…”

Section: Discussionmentioning

confidence: 99%

“…Homeobox protein ZEB2 is functioning as an oncogene in human laryngeal squamous cell carcinoma and acts as an upstream positive regulator of ETS1 (ETS proto-oncogene 1) (Li et al 2019;Yalim-Camci et al 2019). Furthermore, transcription factor ETS1 is coexpressed with ZEB2 and mediates ZEB2-induced epithelial-mesenchymal transition in human tumors (Yalim-Camci et al 2019). At the same time, transcription factor ZEB2 regulates the activity of ETS1 by directly binding to its promoter.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, it was shown that transcriptional inhibitor ZEB2 (zinc finger E-box binding homeobox 2) functions as oncogene in human laryngeal squamous cell carcinoma (Li et al 2019). Furthermore, transcription factor ETS1 (ETS proto-oncogene 1) is coexpressed with ZEB2 and mediates ZEB2-induced epithelialmesenchymal transition in human tumors (Yalim-Camci et al 2019). Moreover, ZEB2 regulates the activity of ETS1 by direct binding to its promoter, but migration and invasion of tumor cells are regulated by ZEB2-induced ETS1 activity, where ZEB2 acts as an upstream positive regulator of ETS1.…”

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confidence: 99%

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ERN1 knockdown modifies the effect of glucose deprivation on homeobox gene expressions in U87 glioma cells

Tsymbal

Minchenko

Khita

et al. 2020

Endocrine Regulations

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Objective. The aim of the present investigation was to study the expression of genes encoding homeobox proteins ZEB2 (zinc finger E-box binding homeobox 2), TGIF1 (TGFB induced factor homeobox 1), SPAG4 (sperm associated antigen 4), LHX1 (LIM homeobox 1), LHX2, LHX6, NKX3-1 (NK3 homeobox 1), and PRRX1 (paired related homeobox 1) in U87 glioma cells in response to glucose deprivation in control glioma cells and cells with knockdown of ERN1 (endoplasmic reticulum to nucleus signaling 1), the major pathway of the endoplasmic reticulum stress signaling, for evaluation of it possible significance in the control of glioma growth through ERN1 signaling and chemoresistance.Methods. The expression level of homeobox family genes was studied in control (transfected by vector) and ERN1 knockdown U87 glioma cells under glucose deprivation condition by real-time quantitative polymerase chain reaction.Results. It was shown that the expression level of ZEB2, TGIF1, PRRX1, and LHX6 genes was up-regulated in control glioma cells treated by glucose deprivation. At the same time, the expression level of three other genes (NKX3-1, LHX1, and LHX2) was down-regulated. Furthermore, ERN1 knockdown of glioma cells significantly modified the effect glucose deprivation condition on the expression almost all studied genes. Thus, treatment of glioma cells without ERN1 enzymatic activity by glucose deprivation condition lead to down-regulation of the expression level of ZEB2 and SPAG4 as well as to more significant up-regulation of PRRX1 and TGIF1 genes. Moreover, the expression of LHX6 and NKX3-1 genes lost their sensitivity to glucose deprivation but LHX1 and LHX2 genes did not change it significantly.Conclusions. The results of this investigation demonstrate that ERN1 knockdown significantly modifies the sensitivity of most studied homeobox gene expressions to glucose deprivation condition and that these changes are a result of complex interaction of variable endoplasmic reticulum stress related and unrelated regulatory factors and contributed to glioma cell growth and possibly to their chemoresistance.

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ETS1 is coexpressed with ZEB2 and mediates ZEB2‐induced epithelial‐mesenchymal transition in human tumors

Cited by 29 publications

References 63 publications

Transcription Factors in Cancer Development and Therapy

Transcription Factors in Cancer Development and Therapy

A Computational Model of the Endothelial to Mesenchymal Transition

ERN1 knockdown modifies the effect of glucose deprivation on homeobox gene expressions in U87 glioma cells

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