EZH2 represses mesenchymal genes and upholds epithelial identity in breast cancer cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1036273 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Emerging studies support that the Polycomb Repressive Complex 2 (PRC2) regulates phenotypic changes of cancer cells by modulating their shifts among metastable states within the epithelial and mesenchymal spectrum. This new role of PRC2 in cancer has been recently proposed to stem from the ability of its catalytic subunit EZH2 to bind and modulate the transcription of a large set of mesenchymal genes during epithelial-mesenchymal transition (EMT) in lung cancer cells. Here, we asked whether this mechanism is conserved across different types of carcinomas. By combining TGF-β-mediate reversible induction of epithelial to mesenchymal transition and pharmacological inhibition of EZH2 activity we demonstrate that EZH2 represses a large set of mesenchymal genes and favours the residence of breast cancer cells towards the more epithelial spectrum during EMT in breast cancer cells.
2024-07-26 | GSE247138 | GEO
Project description:The multi-step process of epithelial to mesenchymal transition (EMT), whereby static epithelial cells become migratory mesenchymal cells, is heavily involved in development, wound healing, and disease states. Despite the major involvement of basic helix-loop-helix (bHLH) transcription factors (TFs) in cell-fate determination, few have examined them for their involvement in fundamental processes that require EMT. Here, we have identified Max network transcription repressor (MNT) as a potent EMT promoting TF in mammary epithelium. We show that depletion of MNT blocked TGF?-induced phenotypic changes, and transcriptomic analysis revealed that MNT is a transcription repressor of epithelial identity. We show that MNT mediates repression of epithelial identity via direct interaction with HDAC1. Lastly, we show that MNT and its target genes are heavily expressed in EMT-High breast cancer, with MNT required for breast cancer cell migration. Taken together, these findings establish MNT as a critical regulator of cell-fate determination and the EMT transcriptome.
2021-09-29 | GSE158546 | GEO
Project description:Emerging studies support that the polycomb repressive complex 2 (PRC2) regulates phenotypic changes of carcinoma cells by modulating their shifts among metastable states within the epithelial and mesenchymal spectrum. This new role of PRC2 in cancer has been recently proposed to stem from the ability of its catalytic subunit EZH2 to bind and modulate the transcription of mesenchymal genes during epithelial-mesenchymal transition (EMT) in lung cancer cells. Here, we asked whether this mechanism is conserved in other types of carcinomas. By combining TGF-β-mediated reversible induction of epithelial to mesenchymal transition and inhibition of EZH2 methyltransferase activity, we demonstrate that EZH2 represses a large set of mesenchymal genes and favours the residence of breast cancer cells towards the more epithelial spectrum during EMT. In agreement, analysis of human patient samples supports that EZH2 is required to efficiently repress mesenchymal genes in breast cancer tumours. Our results indicate that PRC2 operates through similar mechanisms in breast and lung cancer cells. We propose that PRC2-mediated direct transcriptional modulation of the mesenchymal gene expression programme is a conserved molecular mechanism underlying cell dissemination across human carcinomas.
| S-EPMC11341823 | biostudies-literature
Project description:The mechanisms regulating breast cancer differentiation state are poorly understood. Of particular interest are molecular regulators controlling the highly aggressive and poorly differentiated traits of basal-like breast carcinomas. Here we show that the Polycomb factor EZH2 maintains the differentiation state of basal-like breast cancer cells, and promotes the expression of progenitor-associated and basal-lineage genes. Specifically, EZH2 regulates the composition of basal-like breast cancer cell populations by promoting a M-bM-^@M-^\bi-lineageM-bM-^@M-^] differentiation state, in which cells co-express basal- and luminal-lineage markers. We show that human basal-like breast cancers contain a subpopulation of bi-lineage cells, and that EZH2-deficient cells give rise to tumors with a decreased proportion of such cells. Bi-lineage cells express genes that are active in normal luminal progenitors, and possess increased colony formation capacity, consistent with a primitive differentiation state. We found that GATA3, a driver of luminal differentiation, performs a function opposite to EZH2, acting to suppress bi-lineage identity and luminal progenitor gene expression. GATA3 levels increase upon EZH2 silencing, leading to the observed decrease in bi-lineage cell numbers. Our findings reveal a novel role for EZH2 in controlling basal-like breast cancer differentiation state and intra-tumoral cell composition. Total of four treatments (HCC70 cells stably expressing shEZH2, shEED, or EZH2 cDNA, and MDA-MB-468 cells stably expressing shEZH2) were done in duplicates, each with its own control.
2012-09-21 | E-GEOD-36939 | biostudies-arrayexpress
Project description:To determine the mesenchymal function of EZH2 in the mouse uterus, we generated Ezh2 cKO mice using anti-Mullerian hormone type 2 (Amhr2)-Cre that is expressed in the mesenchymal and not epithelial compartment of the uterus
2022-12-28 | GSE201973 | GEO
Project description:Background: Precise spatiotemporal control of gene expression is essential for the establishment of correct cell numbers and identities during brain development. This process involves epigenetic control mechanisms, such as those mediated by the polycomb group protein Ezh2 that catalyzes trimethylation of histone H3K27 (H3K27me3) and thereby represses gene expression. Results: Here we show that Ezh2 plays a crucial role in development and maintenance of the midbrain. Conditional deletion of Ezh2 in the developing midbrain resulted in decreased neural progenitor proliferation, which is associated with derepression of cell cycle inhibitors and negative regulation of Wnt/beta-catenin signaling. Of note, Ezh2 ablation also promoted ectopic expression of a forebrain transcriptional program involving derepression of the forebrain determinants Foxg1 and Pax6. This was accompanied by reduced expression of midbrain markers, including Pax3 and Pax7, as a consequence of decreased Wnt/beta-catenin signaling. Conclusion: Ezh2 is required for appropriate brain growth and for maintenance of regional identity by H3K27me3-mediated gene repression and control of canonical Wnt signaling. After tissue isolation from dorsal midbrains of embryonic day (E) 10.5 embryos, total RNA was isolated with the RNAeasy kit (Qiagen) and RNase-Free DNase Set (79254, Qiagen) following the manufacturer's instructions. Isolated total RNA of E10.5 control (n=3, from 2 different litters) and Ezh2 cko (n=3, from 2 different litters) dorsal midbrains was used for microarray analysis performed at the Functional Genomics Center Zurich (FGCZ), Switzerland, using the Affymetrix A430 platform.
2015-11-09 | E-GEOD-74538 | biostudies-arrayexpress
Project description:Mesenchymal EZH2 maintains uterine adenogenic homeostasis
| PRJNA833877 | ENA
Project description:EZH2 plays an important role in stem cell renewal and maintenance by inducing gene silencing via its histone methyltransferase activity. EZH2 downregulation markedly enhances neuron differentiation of human mesenchymal stem cells (hMSCs)chromatin at promoters of EZH2 target genes. comparison of knockdown EZH2 of hMSCs vs hMSCs
2012-12-05 | E-GEOD-42687 | biostudies-arrayexpress
Project description:The mechanisms regulating breast cancer differentiation state are poorly understood. Of particular interest are molecular regulators controlling the highly aggressive and poorly differentiated traits of basal-like breast carcinomas. Here we show that the Polycomb factor EZH2 maintains the differentiation state of basal-like breast cancer cells, and promotes the expression of progenitor-associated and basal-lineage genes. Specifically, EZH2 regulates the composition of basal-like breast cancer cell populations by promoting a “bi-lineage” differentiation state, in which cells co-express basal- and luminal-lineage markers. We show that human basal-like breast cancers contain a subpopulation of bi-lineage cells, and that EZH2-deficient cells give rise to tumors with a decreased proportion of such cells. Bi-lineage cells express genes that are active in normal luminal progenitors, and possess increased colony formation capacity, consistent with a primitive differentiation state. We found that GATA3, a driver of luminal differentiation, performs a function opposite to EZH2, acting to suppress bi-lineage identity and luminal progenitor gene expression. GATA3 levels increase upon EZH2 silencing, leading to the observed decrease in bi-lineage cell numbers. Our findings reveal a novel role for EZH2 in controlling basal-like breast cancer differentiation state and intra-tumoral cell composition.
2012-09-21 | GSE36939 | GEO
Project description:Background: Precise spatiotemporal control of gene expression is essential for the establishment of correct cell numbers and identities during brain development. This process involves epigenetic control mechanisms, such as those mediated by the polycomb group protein Ezh2 that catalyzes trimethylation of histone H3K27 (H3K27me3) and thereby represses gene expression. Results: Here we show that Ezh2 plays a crucial role in development and maintenance of the midbrain. Conditional deletion of Ezh2 in the developing midbrain resulted in decreased neural progenitor proliferation, which is associated with derepression of cell cycle inhibitors and negative regulation of Wnt/β-catenin signaling. Of note, Ezh2 ablation also promoted ectopic expression of a forebrain transcriptional program involving derepression of the forebrain determinants Foxg1 and Pax6. This was accompanied by reduced expression of midbrain markers, including Pax3 and Pax7, as a consequence of decreased Wnt/β-catenin signaling. Conclusion: Ezh2 is required for appropriate brain growth and for maintenance of regional identity by H3K27me3-mediated gene repression and control of canonical Wnt signaling.
2015-11-09 | GSE74538 | GEO