ArticleCancer research2013
Epithelial-mesenchymal transition and tumor suppression are controlled by a reciprocal feedback loop between ZEB1 and Grainyhead-like-2.
Article in Cancer research, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 121 papers.
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Who cites it
121 citing papers in PubMed, 211 citations in OpenAlex.
- Fluctuating environment causes neoplastic transition and epithelial-mesenchymal plasticity in human cells.Research square · 2026Article
- Spatial transcriptomic profiling of ovarian clear cell carcinoma reveals heterogeneity in OXPHOS and EMT gradients.Nature communications · 2026Article
- Defining the DNA Binding Specificity of GRHL2.bioRxiv : the preprint server for biology · 2026Article
- Mesenchymal to epithelial transition (MET) in cancer progression: insights from logical modeling.Scientific reports · 2026Article
- KMT2C and KMT2D amplify GRHL2-driven enhancer activation.bioRxiv : the preprint server for biology · 2026Article
- Role and Mechanism ofInternational journal of molecular sciences · 2026Article
- Implication of Epigenetic Alterations of ZEB1 in Colorectal Cancer (CRC) Pathogenesis and Therapy Development.Current issues in molecular biology · 2026Review
- Unraveling the anoikis-cancer nexus: a bibliometric analysis of research trends and mechanisms.Future science OA · 2025Article
- Stemness regulation in prostate cancer: prostate cancer stem cells and targeted therapy.Annals of medicine · 2025Review
- A positive feedback loop between TNS1 and ZEB1 promotes TGFβ-induced epithelial-to-mesenchymal transition in lung cancer.Communications biology · 2025Article
- SIX1 transmits signals for breast cancer progression via the ZEB1/IL6/STAT3 signaling axis.Oncogene · 2025Article
- The Role of Epithelial-Mesenchymal Transition in Osteosarcoma Progression: From Biology to Therapy.Diagnostics (Basel, Switzerland) · 2025Review
- Article
- An integrated omics approach highlights how epigenetic events can explain and predict response to neoadjuvant chemotherapy and bevacizumab in breast cancer.Molecular oncology · 2024Article
- Exploring the reciprocity between pioneer factors and development.Development (Cambridge, England) · 2024Review
- Grainyhead-like-2, an epithelial master programmer, promotes interferon induction and suppresses breast cancer recurrence.Molecular immunology · 2024Article
- GRHL2 suppression of NT5E/CD73 in breast cancer cells modulates CD73-mediated adenosine production and T cell recruitment.iScience · 2024Article
- A Novel Methylation-based Model for Prognostic Prediction in Lung Adenocarcinoma.Current genomics · 2024Article
- An estrogen-regulated long non-coding RNA NCALD promotes luminal breast cancer proliferation by activating GRHL2.Cancer cell international · 2024Article
- Article
61 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Epithelial-mesenchymal transition (EMT) in carcinoma cells enhances malignant progression by promoting invasion and survival. EMT is induced by microenvironmental factors, including TGF-β and Wnt agonists, and by the E-box-binding transcription factors Twist, Snail, and ZEB. Grainyhead-like-2 (GRHL2), a member of the mammalian Grainyhead family of wound-healing regulatory transcription factors, suppresses EMT and restores sensitivity to anoikis by repressing ZEB1 expression and inhibiting TGF-β signaling. In this study, we elucidate the functional relationship between GRHL2 and ZEB1 in EMT/MET and tumor biology. At least three homeodomain proteins, Six1, LBX1, and HoxA5, transactivated the ZEB1 promoter, in the case of Six1, through direct protein-promoter interaction. GRHL2 altered the Six1-DNA complex, inhibiting this transactivation. Correspondingly, GRHL2 expression prevented tumor initiation in xenograft assays, sensitized breast cancer cells to paclitaxel, and suppressed the emergence of CD44(high)CD24(low) cells (defining the cancer stem cell phenotype in the cell type studied). GRHL2 was downregulated in recurrent mouse tumors that had evolved to an oncogene-independent, EMT-like state, supporting a role for GRHL2 downregulation in this phenotypic transition, modeling disease recurrence. The combination of TGF-β and Wnt activation repressed GRHL2 expression by direct interaction of ZEB1 with the GRHL2 promoter, inducing EMT. Together, our observations indicate that a reciprocal feedback loop between GRHL2 and ZEB1 controls epithelial versus mesenchymal phenotypes and EMT-driven tumor progression.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.