Novel Strategies to Enforce an Epithelial Phenotype in Mesenchymal Cells

Dragoi, Ana‐Maria; Swiss, Rachel; Gao, Beile; Agaisse, Hervé

doi:10.1158/0008-5472.can-13-3231

Cited by 20 publications

(29 citation statements)

References 55 publications

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“…16 Moreover, we found that FLASH is regulating ZEB1 protein expression while ZEB1 mRNA level remained largely unchanged. Reduced ZEB1 expression in cancer cells resulted in de-repression of multiple ZEB1-regulated genes involved in maintenance of the epithelial phenotype.…”

Section: Discussionmentioning

confidence: 75%

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

2016

Oncogenesis

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Cancer metastasis remains a significant challenge and the leading cause of cancer-associated deaths. It is postulated that during metastasis cells undergo epithelial-to-mesenchymal transition (EMT), a process characterized by loss of cell–cell contacts and increased migratory and invasive potential. ZEB1 is one the most prominent transcriptional repressors of genes associated with EMT. We identified caspase-8-associated protein 2 (CASP8AP2 or FLASH) as a novel posttranscriptional regulator of ZEB1. Here we demonstrate that FLASH protects ZEB1 from proteasomal degradation brought by the action of the ubiquitin ligases SIAH1 and F-box protein FBXO45. As a result, loss of FLASH rapidly destabilized ZEB1 and reversed EMT cellular characteristics. Importantly, loss of FLASH blocked transforming growth factor-β-induced EMT and enhanced sensitivity to chemotherapy. Thus, we propose that FLASH–ZEB1 interplay may be a protective mechanism against ZEB1 degradation in cells undergoing EMT and may be an efficacious target for therapies aimed to block EMT progression.

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Section: Discussionmentioning

confidence: 75%

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

2016

Oncogenesis

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“…In lung and pancreatic cancer cells, sensitivity to therapeutic agents can be increased by promoting an epithelial phenotype (Witta et al, 2006;Arumugam et al, 2009;Buonato and Lazzara, 2014). These findings have motivated studies to decipher the signaling and regulatory mechanisms underlying EMT (Davis et al, 2014;Dragoi et al, 2014;Wilson et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

EGF augments TGFβ-induced epithelial–mesenchymal transition by promoting SHP2 binding to GAB1

Buonato

Lan

Lazzara

2015

Journal of Cell Science

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In many epithelial cells, epidermal growth factor (EGF) augments the epithelial-mesenchymal transition (EMT) that occurs when cells are treated with transforming growth factor β (TGFβ). We demonstrate that this augmentation requires activation of SH2 domain-containing phosphatase-2 (SHP2; also known as PTPN11), a proto-oncogene. In lung and pancreatic cancer cell lines, reductions in E-cadherin expression, increases in vimentin expression and increases in cell scatter rates were larger when cells were treated with TGFβ and EGF versus TGFβ or EGF alone. SHP2 knockdown promoted epithelial characteristics basally and antagonized EMT in response to TGFβ alone or in combination with EGF. Whereas EGF promoted SHP2 binding to tyrosine phosphorylated GAB1, which promotes SHP2 activity, TGFβ did not induce SHP2 association with phosphotyrosine-containing proteins. Knockdown of endogenous SHP2 and reconstitution with an SHP2 mutant with impaired phosphotyrosine binding ability eliminated the EGF-mediated EMT augmentation that was otherwise restored with wild-type SHP2 reconstitution. These results demonstrate roles for basal and ligandinduced SHP2 activity in EMT and further motivate efforts to identify specific ways to inhibit SHP2, given the role of EMT in tumor dissemination and chemoresistance.

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“…FBXL5 may promote epithelial-to-mesenchymal transition (EMT) by mediating E-cadherin degradation [94], consistent with a role for FBXL5 in regulating cancer metastasis. However, Snail1, an EMT-promoting transcription factor, was reported to be degraded by FBXL5-dependent pathway in the nucleus [95].…”

Section: Mirna-dependent Regulation Of F-box Proteins and Its Rolementioning

confidence: 80%

MicroRNA regulation of F-box proteins and its role in cancer

Pfeffer

2016

Seminars in Cancer Biology

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MicroRNAs (miRNAs) are small endogenous non-coding RNAs, which play critical roles in cancer development by suppressing gene expression at the post-transcriptional level. In general, oncogenic miRNAs are upregulated in cancer, while miRNAs that act as tumor suppressors are downregulated, leading to decreased expression of tumor suppressors and upregulated oncogene expression, respectively. F-box proteins function as the substrate-recognition components of the SKP1-CUL1-F-box (SCF)-ubiquitin ligase complex for the degradation of their protein targets by the ubiquitin-proteasome system. Therefore F-box proteins and miRNAs both negatively regulate target gene expression post-transcriptionally. Since each miRNA is capable of fine-tuning the expression of multiple target genes, multiple F-box proteins may be suppressed by the same miRNA. Meanwhile, one F-box proteins could be regulated by several miRNAs in different cancer types. In this review, we will focus on miRNA-mediated downregulation of various F-box proteins, the resulting stabilization of F-box protein substrates and the impact of these processes on human malignancies. We provide insight into how the miRNA: F-box protein axis may regulate cancer progression and metastasis. We also consider the broader role of F-box proteins in the regulation of pathways that are independent of the ubiquitin ligase complex and how that impacts on oncogenesis. The area of miRNAs and the F-box proteins that they regulate in cancer is an emerging field and will inform new strategies in cancer treatment.

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Novel Strategies to Enforce an Epithelial Phenotype in Mesenchymal Cells

Cited by 20 publications

References 55 publications

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

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

EGF augments TGFβ-induced epithelial–mesenchymal transition by promoting SHP2 binding to GAB1

MicroRNA regulation of F-box proteins and its role in cancer

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