ZEB1-induced tumourigenesis requires senescence inhibition via activation of DKK1/mutant p53/Mdm2/CtBP and repression of macroH2A1

Barrios, Oriol de; Győrffy, Balázs; Fernández-Aceñero, María Jesús; Sánchez-Tilló, Ester; Sanchez‐Moral, Lidia; Siles, Laura; Esteve-Arenys, Anna; Roué, Gaël; Casal, J. Ignacio; Darling, Douglas S.; Castells, Antoni; Postigo, Antonio

doi:10.1136/gutjnl-2015-310838

Cited by 38 publications

(41 citation statements)

References 59 publications

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“…A previous study demonstrated that ZEB1 expression enhanced the aggressive tumour cell phenotype by remodelling lung cancer extracellular matrix . ZEB1 expression also promoted tumour initiation and progression, which resulted from inhibiting the senescence of colorectal cancer cells . The current study demonstrated that ZEB1 was significantly correlated with Gleason score, TNM and metastasis, in a manner similar to VM.…”

Section: Discussionsupporting

confidence: 68%

ZEB1‐mediated vasculogenic mimicry formation associates with epithelial–mesenchymal transition and cancer stem cell phenotypes in prostate cancer

Wang

Huang

et al. 2018

J Cellular Molecular Medi

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The zinc finger E‐box‐binding homeobox 1 (ZEB1) induced the epithelial–mesenchymal transition (EMT) and altered ZEB1 expression could lead to aggressive and cancer stem cell (CSC) phenotypes in various cancers. Tissue specimens from 96 prostate cancer patients were collected for immunohistochemistry and CD34/periodic acid–Schiff double staining. Prostate cancer cells were subjected to ZEB1 knockdown or overexpression and assessment of the effects on vasculogenic mimicry formation in vitro and in vivo. The underlying molecular events of ZEB1‐induced vasculogenic mimicry formation in prostate cancer were then explored. The data showed that the presence of VM and high ZEB1 expression was associated with higher Gleason score, TNM stage, and lymph node and distant metastases as well as with the expression of vimentin and CD133 in prostate cancer tissues. Furthermore, ZEB1 was required for VM formation and altered expression of EMT‐related and CSC‐associated proteins in prostate cancer cells in vitro and in vivo. ZEB1 also facilitated tumour cell migration, invasion and clonogenicity. In addition, the effects of ZEB1 in prostate cancer cells were mediated by Src signalling; that is PP2, a specific inhibitor of the Src signalling, dose dependently reduced the p‐Src527 level but not p‐Src416 level, while ZEB1 knockdown also down‐regulated the level of p‐Src527 in PC3 and DU‐145 cells. PP2 treatment also significantly reduced the expression of VE‐cadherin, vimentin and CD133 in these prostate cancer cells. Src signalling mediated the effects of ZEB1 on VM formation and gene expression.

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Section: Discussionsupporting

confidence: 68%

ZEB1‐mediated vasculogenic mimicry formation associates with epithelial–mesenchymal transition and cancer stem cell phenotypes in prostate cancer

Wang

Huang

et al. 2018

J Cellular Molecular Medi

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“…The development of detection techniques for cSCCs has enabled the timely treatment of this disease, resulting in an increase in the survival rate of patients with cSCCs [23]. Recently, the dysregulation of CtBP expression has been considered a key step in the formation of various human tumors [24][25][26]. K/o of CtBP can increase the induction of apoptosis and inhibit tumorigenesis in vivo [27,28].…”

Section: Discussionmentioning

confidence: 99%

The C-terminal of the E1A binding protein 2 enhances the metastatic potential of keratinocyte-derived cutaneous squamous carcinoma cells via the gp130/JAK2/Stat1 signaling pathway

Zuo

Bao

et al. 2020

Preprint

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Background The abnormal expression of C-terminal of the E1A binding proteins (CtBPs) was is observed to be involved in several human tumors. This study aims to investigate the expression of CtBPs and their potential underlying mechanisms in the most common metastatic skin cancer, keratinocyte-derived cutaneous squamous cell carcinoma (cSCCs) patients and their evaluation value in clinical diagnosis and prognosis. Methods In the present study, the expression levels of CtBPs in cSCCs and actinic keratosis tissues were examined by immunohistochemical assay. To discover the effects of CtBP2 on the metastatic phenotype of cSCCs, a stably expressing plasmid was transfected into keratinocyte cells in order to initiate CtBP2 overexpression. The endogenous protein gp130, which is a signal-transducing subunit associated with the ligand-occupied interleukin receptor was silenced in these cells using short hairpin RNA (shRNA) sequences. Moreover, the endogenous expression of CtBP2 in cSCCs cell lines was also silenced. Transfection efficiency was validated by western blotting and immunofluorescence assays, and the malignant phenotype of these cells was evaluated by various assays including the CCK8, colony formation, transwell, and cell scratch assay. Furthermore, the activation state of the gp130/JAK2/Stat1 signaling pathway was further discovered via western blotting. Results The observation discovered that the mean levels of CtBP2 expression, not noted for CtBP1, were elevated in 104 cSCCs tissue samples compared with those noted in 102 actinic keratosis tissue samples. The upregulated expression levels of CtBP2 were remarkably associated with tumor metastasis. CtBP2 promoted the malignant phenotype of keratinocyte cells, and gp130 knockdown (k/o) notably reduced this effect in keratinocyte cells by inhibiting the activation of the JAK2/Stat1 pathway. In addition, the k/o of CtBP2 notably reduced the ability of cSCCs cells to metastasize by suppressing the gp130/JAK2/Stat1 pathway. Conclusions The present data revealed that CtBP2 promoted cSCCs cell metastasis via the gp130/JAK2/Stat1 pathway, suggesting that targeting of CtBP2 or gp130 is a promising anti-tumor tactics to impede tumor progression in cSCCs.

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“…Inhibition of H2AFY induces tumorigenicity and expression of the transcription factor ZEB1, which leads to a poor prognosis in patients with colon cancer (24). However, in some studies, H2AFY has been shown to be carcinogenic.…”

Section: Introductionmentioning

confidence: 99%

The diagnostic and prognostic value of H2AFY in hepatocellular carcinoma

Ding

Zeng

2020

Preprint

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Background The potential correlation between H2AFY (also known as MacroH2A1) and the clinical characteristics of hepatocellular carcinoma (HCC) patients was analysed through gene expression profiles and clinical data in The Cancer Genome Atlas (TCGA) database, and the diagnostic and prognostic value of H2AFY in HCC was discussed. Methods The gene expression data of HCC and the corresponding clinical characteristics of HCC patients were downloaded from the TCGA database. The differences in H2AFY in normal liver tissues and HCC were analysed. The relationship between H2AFY and clinical characteristics was analysed by Wilcoxon signed-rank test, logistic regression and Kruskal-Wallis test. The Kaplan-Meier method and the Cox regression method were used to analyse the relationship between overall survival and clinical characteristics of the patients. An ROC curve was used to predict the diagnostic value of H2AFY in HCC. Gene set enrichment analysis (GSEA) was used to analyse the pathway enrichment of H2AFY. Result Compared with normal liver tissues, H2AFY was significantly highly expressed in HCC. H2AFY was positively correlated with the age, clinical stage, G stage and T stage of liver cancer patients. Higher H2AFY expression predicted a poor prognosis in HCC patients. Cox regression analysis suggested that H2AFY was an independent risk factor for the prognosis of HCC patients. The ROC curve suggested that H2AFY had certain diagnostic value in HCC. GSEA suggested that H2AFY was correlated with lipid metabolism and a variety of tumour pathways. Conclusion Our study showed that H2AFY was significantly overexpressed in HCC. H2AFY may be a potential diagnostic and prognostic marker for HCC, and high expression of H2AFY predicts a poor prognosis in patients with HCC.

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ZEB1-induced tumourigenesis requires senescence inhibition via activation of DKK1/mutant p53/Mdm2/CtBP and repression of macroH2A1

Abstract: The tumourigenic capacity of ZEB1 depends on its inhibition of cancer cell senescence through the activation of a herein identified new molecular pathway. These results set ZEB1 as a potential target in therapeutic strategies aimed at inducing senescence.

Cited by 38 publications

References 59 publications

ZEB1‐mediated vasculogenic mimicry formation associates with epithelial–mesenchymal transition and cancer stem cell phenotypes in prostate cancer

ZEB1‐mediated vasculogenic mimicry formation associates with epithelial–mesenchymal transition and cancer stem cell phenotypes in prostate cancer

The C-terminal of the E1A binding protein 2 enhances the metastatic potential of keratinocyte-derived cutaneous squamous carcinoma cells via the gp130/JAK2/Stat1 signaling pathway

The diagnostic and prognostic value of H2AFY in hepatocellular carcinoma

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