Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Epigenetic regulation of chromosomal instability by EZH2 methyltransferase [CUT&RUN]

ABSTRACT: Chromosomal instability (CIN) and epigenetic alterations, major drivers of tumor evolution, contribute to breast cancer metastasis. Whether CIN is epigenetically regulated in metastatic cells is poorly understood. Here we show that EZH2 expression is highly correlated with genomic copy number alterations across human breast tumors. Consistently, increased expression of EZH2 histone methyl transferase is associated with elevated CIN in triple negative breast cancer (TNBC) metastasis initiating cells. Genetic or pharmacological inhibition of EZH2 suppresses CIN whereas forced overexpression of EZH2 in otherwise non-transformed cells promotes chromosome segregation errors. Integrated global chromatin and transcriptome profiling identified Tankyrase (TNKS), a multifunctional poly (ADP ribose) polymerase (PARP), as a direct target of EZH2 transcriptional suppressive activity. Strikingly, depletion of TNKS was sufficient to abrogate the ability of EZH2 inhibition to suppress CIN. EZH2-mediated suppression of TNKS induced centrosome amplification and multipolar mitosis which often clustered into pseudo-bipolar mitotic spindles exhibiting chromosome segregation defects. Our work establishes a previously unappreciated epigenetic regulatory mechanisms of CIN and suggests that CIN suppression might be an important component of epigenetic modifying therapies such as EZH2 inhibitors which are currently in clinical use.

ORGANISM(S): Mus musculus

PROVIDER: GSE254324 | GEO | 2025/09/24

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Epigenetic regulation of chromosomal instability by EZH2 methyltransferase [RNA-seq]

Project description:Chromosomal instability (CIN) and epigenetic alterations, major drivers of tumor evolution, contribute to breast cancer metastasis. Whether CIN is epigenetically regulated in metastatic cells is poorly understood. Here we show that EZH2 expression is highly correlated with genomic copy number alterations across human breast tumors. Consistently, increased expression of EZH2 histone methyl transferase is associated with elevated CIN in triple negative breast cancer (TNBC) metastasis initiating cells. Genetic or pharmacological inhibition of EZH2 suppresses CIN whereas forced overexpression of EZH2 in otherwise non-transformed cells promotes chromosome segregation errors. Integrated global chromatin and transcriptome profiling identified Tankyrase (TNKS), a multifunctional poly (ADP ribose) polymerase (PARP), as a direct target of EZH2 transcriptional suppressive activity. Strikingly, depletion of TNKS was sufficient to abrogate the ability of EZH2 inhibition to suppress CIN. EZH2-mediated suppression of TNKS induced centrosome amplification and multipolar mitosis which often clustered into pseudo-bipolar mitotic spindles exhibiting chromosome segregation defects. Our work establishes a previously unappreciated epigenetic regulatory mechanisms of CIN and suggests that CIN suppression might be an important component of epigenetic modifying therapies such as EZH2 inhibitors which are currently in clinical use.

2025-09-24 | GSE254325 | GEO

Chromosomal instability promotes metastasis through a cytosolic DNA response

Project description:Chromosomal instability (CIN) is a hallmark of cancer, and it results from ongoing errors in chromosome segregation during mitosis. While CIN is a major driver of tumor evolution, its role in metastasis has not been established. Here we show that CIN promotes metastasis by sustaining a tumor-cell autonomous inflammatory response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose envelopes frequently rupture exposing their DNA content to the cytosol. This leads to the activation of the cGAS-STING cytosolic DNA-sensing pathway and downstream noncanonical NF-kB signaling. Genetic suppression of CIN significantly delays metastasis in transplantable tumor models, whereas inducing chromosome segregation errors promotes cellular invasion and metastasis in a STING-dependent manner. In contrast to primary tumors, human and mouse metastases strongly select for CIN, in part, due to its ability to enrich for metastasis-initiating mesenchymal subpopulations, offering an opportunity to target chromosome segregation errors for therapeutic benefit.

2018-01-15 | GSE98183 | GEO

Cancer cell non-autonomous tumor progression from chromosomal instability

Project description:Chromosomal instability (CIN) is a driver of cancer metastasis and immune evasion. Yet, the extent to which this effect depends on the immune system remains unknown. Here we show that CIN-induced chronic activation of the cGAS-STING pathway in cancer cells induces signal re-wiring downstream of STING, promoting a pro-metastatic tumor microenvironment (TME). Using ContactTracing, a newly developed, validated, and benchmarked tool to infer conditionally-dependent cell-cell interactions from single cell transcriptomic data, we identify a cancer cell-derived STING-dependent ER stress response that remodels a TME replete with immune suppressive myeloid cells and dysfunctional T cells. Simultaneously, CIN-induced chronic STING activation leads to interferon-specific tach-yphylaxis reinforcing immune suppression. Reversal of CIN, depletion of cancer cell STING, or inhibition of ER stress signaling upends CIN-dependent effects on the TME and suppresses metastasis in immune competent, but not severely immune compromised settings. Treatment with STING inhibitors reduces CIN-driven metastasis in melanoma, breast, and colorectal cancer. Finally, we show that CIN and pervasive cGAS activation in micronuclei are associated with ER stress signaling, immune suppression, and metastasis in human triple-negative breast cancer; highlighting a viable strategy to identify and therapeutically intervene in tumors spurred by CIN-induced inflammation.

2023-06-20 | GSE189856 | GEO

Hypoxa-actived XBP1s recruits HDAC2-EZH2 to engage epigenetic suppression of DNp63 expression and promotes breast cacner metastasis independent HIF1a

Project description:Hypoxia is a hallmark of cancer development. However, the molecular mechanisms by which hypoxia promotes tumor metastasis are not fully understood. In this study, we demonstrate that hypoxia promotes breast cancer metastasis through suppression of ΔNp63α-dependent in a HIF1α-independent manner. We show that hypoxia activates unfolded protein response (UPR) to elevate XBP1s, which in turn forms stable repressor protein complexes with HDAC2 and EZH2 in suppression of ΔNp63α. Notably, while H3K27ac is predominantly presented in the ΔNp63 promoter under normoxia, it is switched to H3K27me3 under hypoxia. We show that XBP1s binds to the ΔNp63 promoter to recruit HDAC2 and EZH2 in facilitating the H3K27ac-H3K27me3 switch. Knockdown or pharmacological inhibition of either HDAC2 or EZH2 leads to increased H3K27ac concomitant with reduced H3K27me3, which effectively restores ΔNp63α expression suppressed by hypoxia, resulting in inhibition of cell migration. Clinical analyses reveal that reduced p63 expression is correlated with the elevated expression of XBP1, HDAC2, or EZH2, and is associated with poor overall survival in human breast cancer patients. Together, these results indicate that hypoxia-activated XBP1s modulates the epigenetic program in suppression of ΔNp63α to promote breast cancer metastasis independent of HIF1α and provides a molecule basis for targeting the XBP1s/HDAC2/EZH2-ΔNp63α axis as a putative strategy in the treatment of breast cancer metastasis.

2024-01-24 | GSE253833 | GEO

Developmentally programmed tankyrase activity upregulates β-catenin and licenses progression of embryonic genome activation

Project description:Embryonic genome activation (EGA) is orchestrated by an intrinsic developmental program initiated during oocyte maturation with translation of stored maternal mRNAs. Here we show that tankyrase, a poly(ADP-ribosyl) polymerase that regulates β-catenin levels, undergoes programmed translation during oocyte maturation and serves an essential role in mouse EGA. Newly translated TNKS triggers proteasomal degradation of axin, reducing targeted destruction of β-catenin and promoting β-catenin-mediated transcription of target genes, including Myc. MYC mediates ribosomal RNA transcription in 2-cell embryos, supporting global protein synthesis. Suppression of tankyrase activity using knockdown or chemical inhibition causes loss of nuclear β-catenin and global reductions in transcription and histone H3 acetylation. Chromatin and transcriptional profiling indicate that development arrests prior to the mid-2-cell stage, mediated in part by reductions in β-catenin and MYC. These findings indicate that post-transcriptional regulation of tankyrase serves as a ligand-independent developmental mechanism for post-translational β-catenin activation and is required to complete EGA.

2020-05-21 | GSE123815 | GEO

A Tissue-Specific Tankyrase Inhibitor Drives Key Developmental and Oncogenic Pathways

Project description:Tissue-specific regulation of WNT and YAP/TAZ signaling is critical for optimal organismal growth, development, and maintenance. Uncontrolled activity often leads to developmental abnormalities and aggressive cancers. Tankyrase (TNKS) is a poly-ADP-ribose polymerase (PARP) that controls both WNT and YAP/TAZ signaling. However, it is unclear how TNKS activity is regulated in a tissue and cell-type specific manner. Here, we identified the previously uncharacterized prostate-associated gene 4 (PAGE4) as a tissue-specific TNKS inhibitor. Structural and biochemical studies revealed that mechanistically PAGE4 inhibits TNKS through hijacking TNKS substrate binding pockets leading to the stabilization of TNKS substrates. In vitro cell culture and in vivo zebrafish and transgenic mouse model studies showed that PAGE4 is a potent inhibitor of TNKS and WNT signaling. Interestingly, PAGE4 is physiologically restricted to expression in select tissues and cell types, including WNT producing prostatic fibroblasts where spatiotemporal regulation of WNT signaling is critical for proper organ development. Surprisingly, PAGE4 is aberrantly expressed in hepatocellular carcinomas that bypass TNKS through mutant CTNNB1 driven WNT signaling. In vitro and in vivo tumorigenic studies revealed that PAGE4 initially function as a tumor suppressor through inhibition of WNT signaling, but upon CTNNB1 mutation becomes an oncogenic driver through YAP/TAZ signaling. Thus, we establish PAGE4 as a robust tissue-specific TNKS inhibitor that physiologically coordinates developmental WNT signaling, but genetic aberration during cancer progression re-wire PAGE4 into pro-oncogenic YAP/TAZ pathway.

2020-12-01 | GSE141323 | GEO

Affinify Purification of EZH2 and phosphodeficient EZH2 identifies phosphorylation dependent interactions of EZH2

Project description:Overexpression of EZH2 in estrogen receptor negative (ER-) breast cancer promotes metastasis. EZH2 has been mainly studied as the catalytic component of the Polycomb Repressive Complex 2 (PRC2) that mediates gene repression by trimethylating histone H3 at lysine 27 (H3K27me3). However, how EZH2 drives metastasis despite the low H3K27me3 levels observed in ER- breast cancer is unknown. We have shown that in human invasive carcinomas and distant metastases, cytoplasmic EZH2 phosphorylated at T367 is significantly associated with ER- disease and low H3K27me3 levels. Here, we explore the interactome of EZH2 and of a phosphodeficient mutant EZH2_T367A. We identified novel interactors of EZH2, and identified interactions that are dependent on the phosphorylation and cellular localization of EZH2 that may play a role in EZH2 dependent metastatic progression.

2018-07-03 | PXD010073 | Pride

Epigenetic Maintenance of Stemness and Malignancy in Peripheral Neuroectodermal Tumors by EZH2

Project description:Chromatin modifications are increasingly recognized as a key mechanism in cancer. The histone methyl-transferase Enhancer of Zeste, Drosophila, Homolog 2 (EZH2) is the enzymatic subunit of the polycomb PRC2 complex and methylates histone H3K27, thereby, mediating gene silencing. Down-regulation of EZH2 by RNA interference in ET suppressed oncogenic transformation, tumor development and metastasis in a respective mouse model. Further microarray analysis of EZH2 knock down, or functionally linked HDAC-inhibitor treatment revealed an undifferentiated reversible phenotype in ET maintained by EZH2. EZH2 suppression resulted in a generalized loss of H3K27me3 as well as an increase in H3 acetylation levels. In addition, ChIP-Chip assays for H3K27me3 identified genes that had specifically lost H3K27me3 upon EZH2 silencing. These findings suggested that stemness features are preserved via epigenetic mechanisms. Taken together, the genetic EWS-Fli1 translocation is intimately linked to global and gene specific epigenetic alterations in ET biology. EZH2 mediates neuroectodermal and endothelial embryonal tumor stem cell growth and metastasic spread induced by a translocation derived chimeric transcription factor. Keywords: PNET, Ewing Tumor Epigenetic regulation A673 transiently transfected with siRNA-EZH2 and siRNA-scrambled were harvested and Chromatin-IPs of H3K27me3 or H3 followed by microarray hybridisation were carried out. For detailed procedures see Burdach et al. Epigenetic Maintenance of Stemness and Malignancy in Peripheral Neuroectodermal Tumors by EZH2.

2010-05-18 | E-GEOD-15890 | biostudies-arrayexpress

Sox4 is a master regulator of epithelial-mesenchymal transition (EMT) by controlling Ezh2 expression and epigenetic reprogramming

Project description:Gene expression profiling has uncovered the transcription factor Sox4 with up-regulated activity during TGFÎ²-induced EMT in normal and cancerous breast epithelial cells. Sox4 is indispensable for EMT and cell survival in vitro and for primary tumor growth and metastasis in vivo. Among several EMT-relevant genes, Sox4 directly regulates the expression of Ezh2, encoding the Polycomb group histone methyltransferase that trimethylates histone 3 lysine 27 (H3K27me3) for gene repression. Ablation of Ezh2 expression prevents EMT, while forced expression of Ezh2 restores EMT in Sox4-deficient cells. Ezh2-mediated H3K27me3 marks associate with key EMT genes, representing an epigenetic EMT signature that predicts patient survival. Our results identify Sox4 as a master regulator of EMT by governing the expression of the epigenetic modifier Ezh2. Our Dataset comprises of 12 ChIP-seq samples using chromatin from NMuMG cells which was immunoprecipitated using H3K27me3-specific antibody during TGFÎ²-induced EMT (2ng/ml) at 6 different stages (day 0, 1, 4, 7, 10, 20).

2013-06-20 | E-GEOD-45579 | biostudies-arrayexpress

Hypoxa-actived XBP1s recruits HDAC2-EZH2 to engage epigenetic suppression of DNp63 expression and promotes breast cacner metastasis independent HIF1a

Project description:Hypoxa-actived XBP1s recruits HDAC2-EZH2 to engage epigenetic suppression of DNp63 expression and promotes breast cacner metastasis independent HIF1a

| PRJNA1067530 | ENA

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data