Poised chromatin at the ZEB1 promoter enables cell plasticity and enhances tumorigenicity
By Christine L. Chaffer, Nemanja Marjanović, T. Lee, George W. Bell, C. Kleer, Ferenc Reinhardt, A. D’Alessio, Richard A. Young, R. Weinberg. Cell, 2013
816 citations recorded by the source corpus.
Summary The recent discovery that normal and neoplastic epithelial cells re-enter the stem-cell state raised an intriguing possibility in the context of cancer pathogenesis: the aggressiveness of carcinomas derives not from their existing content of cancer stem cells (CSCs), but from their proclivity to generate new CSCs from non-CSC populations. Here we demonstrate that non-CSCs of human basal breast cancers are plastic cell populations that readily switch from a non-CSC to CSC-state. The observed cell plasticity is dependent on ZEB1, a key regulator of the epithelial-mesenchymal transition. We find plastic non-CSCs maintain the ZEB1 promoter in a bivalent chromatin configuration enabling them to respond readily to microenvironmental signals, such as TGFbeta. In response, the ZEB1 promoter converts from a bivalent to active chromatin configuration, ZEB1 transcription increases and non-CSCs subsequently enter the CSC state. Our findings support a dynamic model where interconversions between low and high tumorigenic states occur frequently, thereby increasing tumorigenic and malignant potential.
Subfields: Cancer Research, Molecular Biology, Oncology
View Paper: https://www.semanticscholar.org/paper/557657256eedeb8f2b09850691c1b0d5de5ede44
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Citations in the corpus
- Epigenetic Determinants of Cancer. (2016, background): “Yet, others qualify because it is now recognized that promoter CpG island hypermethylation can silence noncoding miRNA genes, which are necessary for modulating signaling networks (Saito and Jones 2006; Saito et al. 2006; Chaffer et al. 2013; Tam and Weinberg 2013; Nickel and Stadler 2014; Sun et al”
- Targeting cancer stem cell pathways for cancer therapy (2020, neutral): “Studies have shown that CAFs promote the EMT and enhance the expression of prostate CSC markers(482) by secreting IL-6 and IL-1β in breast cancer.(483,484) CAFs also secrete TGF-β and activate related pathways to increase ZEB1 transcription, which stimulate lung cancer cells to undergo EMT and CSC t”
- The molecular mechanisms and therapeutic strategies of EMT in tumor progression and metastasis (2022, background): “The expression of ZEB1/2 in epithelial cells causes an EMT and mesenchymal phenotype in tumor stem cells, which promotes invasion, metastatic dissemination, and a dedifferentiated state [69].”
- Epithelial Plasticity: A Common Theme in Embryonic and Cancer Cells (2013, background): “Because the EMT can also endow cells with stem cell properties, and given that cancer can be initiated, maintained, and propagated by stationary and motile cancer stem cells (CSCs) (5, 13), a new field of study has emerged that requires the concerted effort of developmental biologists and Instituto ”
- Reconstructing and reprogramming the tumor propagating potential of glioblastoma stem-like cells (2014, neutral): “For example, recent studies indicate that stem-like cells in breast cancer and melanoma exist in dynamic equilibrium with phenotypically distinct populations incapable of tumor propagation (Chaffer et al., 2013; Roesch et al., 2010).”
- Evolution of the cancer stem cell model. (2014, background): “Indeed, EMT factors have been used to generate T-IC from non-T-IC in breast cancer (Chaffer et al., 2013).”
- Epithelial-Mesenchymal Plasticity: A central regulator of cancer progression (2015, background): “, into a state where they exhibit increases in their tumorinitiating capability (Chaffer et al., 2013).”