FLASH protects ZEB1 from degradation and supports cancer cells' epithelial-to-mesenchymal transition

Cf, Abshire; Jl, Carroll; Am, Dragoi

doi:10.1038/oncsis.2016.55

Cited by 40 publications

(36 citation statements)

References 29 publications

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“…Recent studies indicating that (1) loss of ZEB1 is sufficient to revert an EMT [Abshire et al, ], and that (2) complete MET requires a knockdown of ZEB1 [Das et al, ] further bolster our results. ZEB1 is also responsible for the maintenance of a mesenchymal phenotype [Gregory et al, ].…”

Section: Resultssupporting

confidence: 81%

“…Zinc finger E-box binding homeobox protein 1 (ZEB1) appears to be the most potent transcription factor to be required to actuate an EMT [Das et al, 2009;Gregory et al, 2011;Jolly et al, 2015;Abshire et al, 2016], and in our analysis the only transcription factor to be strongly negatively associated with CDH1 expression in a panel of 877 cell lines from various cancers (including breast, colon, and prostate) ( Table I). Many of the genes from Figure 1 have been shown to be direct ZEB1 targets by ChIP and are enumerated in Figure S1.…”

Section: Grhl2-zeb1 Axis Forms the Core Of Emt Signalingmentioning

confidence: 85%

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The GRHL2/ZEB Feedback Loop-A Key Axis in the Regulation of EMT in Breast Cancer

et al. 2017

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More than 90% of cancer-related deaths are caused by metastasis. Epithelial-to-Mesenchymal Transition (EMT) causes tumor cell dissemination while the reverse process, Mesenchymal-to-Epithelial Transition (MET) allows cancer cells to grow and establish a potentially deadly metastatic lesion. Recent evidence indicates that in addition to E and M, cells can adopt a stable hybrid Epithelial/Mesenchymal (E/M) state where they can move collectively leading to clusters of Circulating Tumor Cells-the "bad actors" of metastasis. EMT is postulated to occur in all four major histological breast cancer subtypes. Here, we identify a set of genes strongly correlated with CDH1 in 877 cancer cell lines, and differentially expressed genes in cell lines overexpressing ZEB1, SNAIL, and TWIST. GRHL2 and ESRP1 appear in both these sets and also correlate with CDH1 at the protein level in 40 breast cancer specimens. Next, we find that GRHL2 and CD24 expression coincide with an epithelial character in human mammary epithelial cells. Further, we show that high GRHL2 expression is highly correlated with worse relapse-free survival in all four subtypes of breast cancer. Finally, we integrate CD24, GRHL2, and ESRP1 into a mathematical model of EMT regulation to validate the role of these players in EMT. Our data analysis and modeling results highlight the relationships among multiple crucial EMT/MET drivers including ZEB1, GRHL2, CD24, and ESRP1, particularly in basal-like breast cancers, which are most similar to triple-negative breast cancer (TNBC) and are considered the most dangerous subtype. J. Cell. Biochem. 118: 2559-2570, 2017. © 2017 Wiley Periodicals, Inc.

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Section: Resultssupporting

confidence: 81%

Section: Grhl2-zeb1 Axis Forms the Core Of Emt Signalingmentioning

confidence: 85%

The GRHL2/ZEB Feedback Loop-A Key Axis in the Regulation of EMT in Breast Cancer

et al. 2017

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“…Previous studies indicated that SIAH1, FBXO45, and ATM can regulate the protein stability of Zeb1 in cancer cells . Our data showed that anti‐Nodal can decrease the expression of ATM, whereas not SIAH1 or FBXO45, in SH‐SY5Y cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Nodal increases the malignancy of childhood neuroblastoma cells via regulation of Zeb1

Cheng

Huang

et al. 2019

BioFactors

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Neuroblastoma (NB) is one of the most common malignant tumors derived from pluripotent cells of the neural crest. Nodal is an important embryonic morphogen which can re-express in cancer cells. The roles of Nodal in the progression of NB are not illustrated. Our present study reveals that Nodal is upregulated in NB cells and tissues. Targeted inhibition of Nodal can suppress the in vitro migration and invasion of NB cells while increase its chemo-sensitivity to doxorubicin (Dox) treatment. Nodal positively regulates the expression of Zeb1, one well-known transcription factors of epithelial to mesenchymal transition (EMT) of cancer cells. Knockdown of Zeb1 can attenuate Nodal-induced malignancy of NB cells. Mechanistically, Nodal increases the protein stability of Zeb1 while has no effect on its mRNA expression. It is due to that Nodal can increase the expression of Ataxia telangiectasia mutated kinase (ATM), which can phosphorylate and stabilize Zeb1 in cancer cells. Collectively, our data revealed that Nodal can increase the malignancy of NB cells via increasing the expression of Zeb1. It suggests that targeted inhibition of Nodal might be a potential therapy approach for NB treatment. © 2019 BioFactors, 45(3): [355][356][357][358][359][360][361][362][363] 2019

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“…Observations in LNCaP and DU145 cells show that ZEB1 mediates the effect of FOXC2 on tumor-initiating potential and drug resistance (Paranjape et al, 2016 ), traits that are often correlated with EMT (Jolly et al, 2014 ; Jolly et al, 2015 ; Mani et al, 2008 ; May et al, 2011 ; Morel et al, 2008 ). Decreased expression of ZEB1 in PANC-1 cells, which express both epithelial and mesenchymal markers (Gradiz et al, 2016 ) and are thus likely to be hybrid E/M cells, results in a complete MET despite upregulation of SLUG and SNAIL in TGF-β treated cells (Abshire et al, 2016 ). Moreover, knockdown of ZEB1, but not necessarily of SNAIL and SLUG, had pronounced effects in cells losing their EMT-like properties (Weitzenfeld et al, n.d. ).…”

Section: Resultsmentioning

confidence: 99%

Distinguishing mechanisms underlying EMT tristability

et al. 2017

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BackgroundThe Epithelial-Mesenchymal Transition (EMT) endows epithelial-looking cells with enhanced migratory ability during embryonic development and tissue repair. EMT can also be co-opted by cancer cells to acquire metastatic potential and drug-resistance. Recent research has argued that epithelial (E) cells can undergo either a partial EMT to attain a hybrid epithelial/mesenchymal (E/M) phenotype that typically displays collective migration, or a complete EMT to adopt a mesenchymal (M) phenotype that shows individual migration. The core EMT regulatory network - miR-34/SNAIL/miR-200/ZEB1 - has been identified by various studies, but how this network regulates the transitions among the E, E/M, and M phenotypes remains controversial. Two major mathematical models – ternary chimera switch (TCS) and cascading bistable switches (CBS) - that both focus on the miR-34/SNAIL/miR-200/ZEB1 network, have been proposed to elucidate the EMT dynamics, but a detailed analysis of how well either or both of these two models can capture recent experimental observations about EMT dynamics remains to be done.ResultsHere, via an integrated experimental and theoretical approach, we first show that both these two models can be used to understand the two-step transition of EMT - E→E/M→M, the different responses of SNAIL and ZEB1 to exogenous TGF-β and the irreversibility of complete EMT. Next, we present new experimental results that tend to discriminate between these two models. We show that ZEB1 is present at intermediate levels in the hybrid E/M H1975 cells, and that in HMLE cells, overexpression of SNAIL is not sufficient to initiate EMT in the absence of ZEB1 and FOXC2.ConclusionsThese experimental results argue in favor of the TCS model proposing that miR-200/ZEB1 behaves as a three-way decision-making switch enabling transitions among the E, hybrid E/M and M phenotypes.Electronic supplementary materialThe online version of this article (10.1186/s41236-017-0005-8) contains supplementary material, which is available to authorized users.

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FLASH protects ZEB1 from degradation and supports cancer cells' epithelial-to-mesenchymal transition

Cited by 40 publications

References 29 publications

The GRHL2/ZEB Feedback Loop-A Key Axis in the Regulation of EMT in Breast Cancer

The GRHL2/ZEB Feedback Loop-A Key Axis in the Regulation of EMT in Breast Cancer

Nodal increases the malignancy of childhood neuroblastoma cells via regulation of Zeb1

Distinguishing mechanisms underlying EMT tristability

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