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EZH2-H3K27me3 mediated KRT14 upregulation promotes TNBC peritoneal metastasis

ABSTRACT: EZH2-H3K27me3 mediated KRT14 upregulation promotes TNBC peritoneal metastasis

PROVIDER: PRJNA899075 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22219994_1.fastq.gz	Fastqsanger.gz
	SRR22219994_2.fastq.gz	Fastqsanger.gz
	SRR22219995_1.fastq.gz	Fastqsanger.gz
	SRR22219995_2.fastq.gz	Fastqsanger.gz
	SRR22219996_1.fastq.gz	Fastqsanger.gz

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EZH2-H3K27me3 mediated KRT14 upregulation promotes TNBC peritoneal metastasis

Project description:Triple-Negative Breast Cancer (TNBC) has a poor prognosis and adverse clinical outcomes among all breast cancer subtypes as there is no available targeted therapy. Overexpression of Enhancer of zeste homolog 2 (EZH2) has been shown to correlate with TNBC's poor prognosis, but the contribution of EZH2 catalytic (H3K27me3) versus non-catalytic EZH2 (NC-EZH2) function in TNBC progression remains elusive. We reveal that selective hyper-activation of functional EZH2 (H3K27me3) over NC-EZH2 alters TNBC metastatic landscape and fosters its peritoneal metastasis, particularly splenic. Instead of H3K27me3-mediated repression of gene expression; here, it promotes KRT14 transcription by attenuating binding of repressor Sp1 to its promoter. Further, KRT14 loss significantly reduces TNBC migration, invasion, and peritoneal metastasis. Consistently, human TNBC metastasis displays positive correlation between H3K27me3 and KRT14 levels. Finally, EZH2 knockdown or H3K27me3 inhibition by EPZ6438 reduces TNBC peritoneal metastasis. Altogether, our preclinical findings suggest a rationale for targeting TNBC with EZH2 inhibitors.

2022-11-10 | GSE217474 | GEO

EZH2-H3K27me3 mediated KRT14 upregulation promotes TNBC peritoneal metastasis.

Project description:Triple-Negative Breast Cancer (TNBC) has a poor prognosis and adverse clinical outcomes among all breast cancer subtypes as there is no available targeted therapy. Overexpression of Enhancer of zeste homolog 2 (EZH2) has been shown to correlate with TNBC's poor prognosis, but the contribution of EZH2 catalytic (H3K27me3) versus non-catalytic EZH2 (NC-EZH2) function in TNBC progression remains elusive. We reveal that selective hyper-activation of functional EZH2 (H3K27me3) over NC-EZH2 alters TNBC metastatic landscape and fosters its peritoneal metastasis, particularly splenic. Instead of H3K27me3-mediated repression of gene expression; here, it promotes KRT14 transcription by attenuating binding of repressor SP1 to its promoter. Further, KRT14 loss significantly reduces TNBC migration, invasion, and peritoneal metastasis. Consistently, human TNBC metastasis displays positive correlation between H3K27me3 and KRT14 levels. Finally, EZH2 knockdown or H3K27me3 inhibition by EPZ6438 reduces TNBC peritoneal metastasis. Altogether, our preclinical findings suggest a rationale for targeting TNBC with EZH2 inhibitors.

| S-EPMC9708848 | biostudies-literature

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

EZH2 inhibition induces HLA class I re-expression in Merkel Cell Carcinoma

Project description:We hypothesized that EZH2 could be involved in immune escape in Merkel Cell Carcinoma (MCC). In this context, we aimed at evaluating whether EZH2 might contribute to HLA-I expression repression in MCC. To this purpose, we first investigated whether low/lack of HLA-I expression is associated with high H3K27me3 levels in MCC tumor samples. Whole proteome analysis of the PeTa cell line by mass spectrometry after DZNeP treatment (EZH2 inhibitor) revealed upregulation of proteins involved in Fc receptor, as well as antigen processing and presentation pathways components.

2023-11-21 | PXD040973 | Pride

An EZH2-NF-kB Regulatory Axis Drives Expression of Pro-Oncogenic Genetic Signatures in TNBC

Project description:EZH2 has been studied most extensively in the context of PRC2-dependent gene repression. Paradoxically, accumulating evidence indicates non-canonical functions for EZH2 in cancer contexts including promoting gene expression in triple negative breast cancer (TNBC) cells through interactions with the transcription factor NF-kB. We define a genomic profile of EZH2 and NF-kB factor RelA, RelB, and NFKB2/p52 co-localization and positive regulation of a subset of NF-kB targets and genes associated with oncogenic functions in TNBC, which is enriched in patient datasets. We demonstrate interaction between EZH2 and RelA requiring the recently identified EZH2 transactivation domain (TAD), which mediates EZH2 recruitment to and activation of certain NF-kB-dependent genes, and supports downstream stemness phenotypes in TNBC cells. Interestingly, EZH2-NF-kB positive regulation of genes and stemness does not require PRC2. This study provides new insight into pro-oncogenic regulatory functions for EZH2 in breast cancer through PRC2-independent, and NF-kB-dependent regulatory mechanisms.

2023-07-10 | GSE223959 | GEO

Chip-chip from HepG2 cells with EZH2, SUZ12 and H3K27me3

Project description:Polycomb group (PcG) proteins including EZH2, SUZ12 and so on, which specifically catalyze trimethylation of histone 3 lysine 27 (H3K27me3), and methylated H3K27 can be recognized by other specific binding proteins to compress chromatin structure, leading to the transcriptional repression of the target genes. To completely understand the epigenetic profile and molecular network of PcG in HCC, we performed ChIP-on-chip screens with EZH2, SUZ12 and H3K27me3 antibodies in HepG2 cells. Comparison of ChIP-on-chip results from EZH2, SUZ12 and H3K27me3.

2013-11-13 | E-GEOD-52300 | biostudies-arrayexpress

Ezh2 and H3K27me3 in cardiomyocytes

Project description:This SuperSeries is composed of the following subset Series: GSE29992: Genome-wide profiling of E12.5 cardiomyocytes RNA expression in both hetozygeous control and mutant GSE29994: ChIP-seq of Ezh2 and H3K27me3 in E12.5 heart apex Refer to individual Series

2012-03-15 | E-GEOD-29997 | biostudies-arrayexpress

Genome-wide analysis of H3K27me3 in Ezh2-conditional iMEFs

Project description:We analyzed the genomic distribution of H3K27me3 in a clone of c-Myc iMEFs (clone C2) either i) wild-type for Ezh2, ii) in the presence of overexpressed exogenous Ezh2, iii) Ezh2-mutant, and iv) Ezh1/Ezh2 pre-deletion (Ezh1/Ezh2 introduced before deletion of endogenous Ezh2) and Ezh2 post-deletion rescue (Ezh2 re-introduced in Ezh2-mutant cells).

2015-10-01 | GSE59293 | GEO

ChIP-seq of Ezh2 and H3K27me3 in E12.5 heart apex

Project description:Ezh2 and H3K27me3 binding sites in E12.5 heart apex PRC2 binding sites in wild type cardiomyocytes

2012-03-15 | E-GEOD-29994 | biostudies-arrayexpress

ChIP-seq of Ezh2 and H3K27me3 in E12.5 heart apex

Project description:Ezh2 and H3K27me3 binding sites in E12.5 heart apex

2012-03-15 | GSE29994 | GEO