ZEB1 turns into a transcriptional activator by interacting with YAP1 in aggressive cancer types

Lehmann, Waltraut; Mossmann, Dirk; Kleemann, Julia; Mock, Kerstin; Meisinger, Chris; Brummer, Tilman; Herr, Ricarda; Brabletz, Simone; Stemmler, Marc P.; Brabletz, Thomas

doi:10.1038/ncomms10498

Cited by 258 publications

(250 citation statements)

References 65 publications

(112 reference statements)

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“…ZEB1 acts as both a transcriptional activator and repressor (Lehmann et al ., 2016; Sanchez‐Tillo et al ., 2011). To clarify the global view of ZEB1‐regulated transcription, we performed RNA‐seq using MDA‐231‐D cells.…”

Section: Resultsmentioning

confidence: 99%

ZEB1‐regulated inflammatory phenotype in breast cancer cells

et al. 2017

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Zinc finger E‐box binding protein 1 (ZEB1) and ZEB2 induce epithelial‐mesenchymal transition (EMT) and enhance cancer progression. However, the global view of transcriptional regulation by ZEB1 and ZEB2 is yet to be elucidated. Here, we identified a ZEB1‐regulated inflammatory phenotype in breast cancer cells using chromatin immunoprecipitation sequencing and RNA sequencing, followed by gene set enrichment analysis (GSEA) of ZEB1‐bound genes. Knockdown of ZEB1 and/or ZEB2 resulted in the downregulation of genes encoding inflammatory cytokines related to poor prognosis in patients with cancer, including IL6 and IL8, therefore suggesting that ZEB1 and ZEB2 have similar functions in terms of the regulation of production of inflammatory cytokines. Antibody array and ELISA experiments confirmed that ZEB1 controlled the production of the IL‐6 and IL‐8 proteins. The secretory proteins regulated by ZEB1 enhanced breast cancer cell proliferation and tumor growth. ZEB1 expression in breast cancer cells also affected the growth of fibroblasts in cell culture, and the accumulation of myeloid‐derived suppressor cells in tumors in vivo. These findings provide insight into the role of ZEB1 in the progression of cancer, mediated by inflammatory cytokines, along with the initiation of EMT.

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Section: Resultsmentioning

confidence: 99%

ZEB1‐regulated inflammatory phenotype in breast cancer cells

et al. 2017

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“…We examined the ability of EphA2 to enhance transcription of known YAP/TAZ-target genes, Cyr61 , Ctgf , and Inhba (16, 19, 43–45) (Fig. 1E).…”

Section: Resultsmentioning

confidence: 99%

The receptor tyrosine kinase EphA2 promotes glutamine metabolism in tumors by activating the transcriptional coactivators YAP and TAZ

et al. 2017

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Malignant tumors reprogram cellular metabolism to support cancer cell proliferation and survival. Although most cancers depend on a high rate of aerobic glycolysis, many cancer cells also display addiction to glutamine. Mounting evidence indicates key roles of glutamine transporters and glutaminase activity in cancer glutamine metabolism. Here, we show that the EphA2 receptor tyrosine kinase activates YAP and TAZ (YAP/TAZ), transcriptional co-activators of the TEAD family of transcription factors, to promote glutamine metabolism in models of HER2-positive breast cancer. EphA2 overexpression induced nuclear accumulation of YAP and TAZ and increased expression of YAP/TAZ target genes. Inhibition of Rho or ROCK kinase abolished EphA2-dependent YAP/TAZ nuclear localization, suggesting Rho signaling as a critical intermediary. Silencing of YAP or TAZ significantly reduced intracellular glutamate, through differential regulation of SLC1A5 and GLS, respectively. Indeed, the regulatory DNA elements of both SLC1A5 and GLS contain TEAD binding sites and were bound by TEAD4 in an EphA2-dependent manner. In human breast cancer, EphA2 expression positively correlates with YAP and TAZ, as well as GLS and SLC1A5. While high expression of EphA2 predicts enhanced metastatic potential and poor survival, increased EphA2 expression rendered HER2-positive breast cancer cells more sensitive to glutaminase inhibition. Together, these findings define a novel mechanism of EphA2-mediated YAP/TAZ activation to promote glutaminolysis through upregulation of GLS and SLC1A5 in HER2+ breast cancer.

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“…[5,6] Further, YAP1 participates in many signaling pathways that regulate organic morphology, including ovary enlargement that is one of the major manifestations of PCOS. Genome-wide association studies (GWAS) showed that the single nucleotide polymorphisms of YAP1 (rs11225161, rs11225138, and rs11225166) were significantly different between PCOS and controls and it appears to be a new susceptibility gene for PCOS.…”

Section: Introductionmentioning

confidence: 99%

Promoter methylation of yes-associated protein (YAP1) gene in polycystic ovary syndrome

et al. 2017

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Background:DNA methylation modification has been proved to influence the phenotype of polycystic ovary syndrome (PCOS). Genome-wide association studies (GWAS) demonstrate that yes-associated protein (YAP1) genetic sites are associated with PCOS. The study aims to detect the methylation status of YAP1 promoter in ovary granulosa cells (GCs) of PCOS patients and explore novel therapeutic targets for PCOS.Methods:Randomized controlled trial was applied and a total of 72 women were included in the study, including 36 cases of PCOS patients and 36 cases of health controls. Ovary GCs were extracted from in vitro fertilization embryo transfer. Methylation status of YAP1 promoter was detected by bisulfite sequencing PCR (BSP). Protein and mRNA expression of YAP1 were measured by western blotting and real-time quantitate PCR.Results:Overall methylation level of YAP1 promoter region from PCOS group was significantly lower than that from control group. CpG sites analysis revealed that 12 sites (−443, −431, −403, −371, −331, −120, −49, −5, +1, +9, +15, +22) were significantly hypomethylated in women with PCOS (P < 0.05). A significant upregulation of YAP1 mRNA and protein expression levels was observed. Testosterone concentration could alleviate the methylation status and demonstrate obvious dose–dependent relation.Conclusion:Our research achievements manifest that hypomethylation of YAP1 promoter promotes the YAP1 expression, which plays a key role in the pathogenesis and accelerate PCOS.

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ZEB1 turns into a transcriptional activator by interacting with YAP1 in aggressive cancer types

Cited by 258 publications

References 65 publications

ZEB1‐regulated inflammatory phenotype in breast cancer cells

ZEB1‐regulated inflammatory phenotype in breast cancer cells

The receptor tyrosine kinase EphA2 promotes glutamine metabolism in tumors by activating the transcriptional coactivators YAP and TAZ

Promoter methylation of yes-associated protein (YAP1) gene in polycystic ovary syndrome

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