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Dual inhibition of EZH1/2 depletes stem cells and over-activates WNT signaling in multiple myeloma

ABSTRACT: Dual inhibition of EZH1/2 depletes stem cells and over-activates WNT signaling in multiple myeloma

PROVIDER: PRJNA431632 | ENA |

REPOSITORIES: ENA

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Dual inhibition of EZH1/2 depletes stem cells and over-activates WNT signaling in multiple myeloma [ChIP-seq]

Project description:Multiple myeloma (MM) is a hematological malignancy caused by accumulation of abnormal clonal plasma cells. Despite the recent development of novel therapies, relapse of MM eventually occurs due to a remaining population of drug-resistant myeloma stem cells. Side population (SP) cells exhibit cancer stem cell-like characteristics in MM; thus targeting these cells is a promising strategy to completely cure this malignancy. Here, we showed that SP cells expressed higher levels of enhancer of zeste (EZH) 1 and EZH2, which encode the catalytic subunits of Polycomb repressive complex 2 (PRC2), than non-SP cells, suggesting that EZH1/2 are both potential therapeutic targets to eradicate myeloma stem cells. A novel EZH1/2 dual inhibitor, OR-S1, effectively eradicated SP cells and had a greater antitumor effect than a selective EZH2 inhibitor in vitro and in vivo, including in a patient-derived xenograft model. Moreover, long-term continuous administration of OR-S1 completely cured mice bearing orthotopic xenografts. Additionally, PRC2 directly regulated WNT signaling, and over-activation of this signaling induced by dual inhibition of EZH1/2 eradicated myeloma stem cells. Our results demonstrate that dual inhibition of EZH1/2 is a promising therapeutic approach to eradicate myeloma stem cells, leading to significant advances in the treatment of MM.

2019-01-25 | GSE109674 | GEO

Dual inhibition of EZH1/2 depletes stem cells and over-activates WNT signaling in multiple myeloma [RNA-seq]

2019-01-25 | GSE109673 | GEO

Dual inhibition of EZH1/2 depletes stem cells and over-activates WNT signaling in multiple myeloma [ChIP-seq]

Project description:Dual inhibition of EZH1/2 depletes stem cells and over-activates WNT signaling in multiple myeloma [ChIP-seq]

| PRJNA431631 | ENA

Dual inhibition of EZH1/2 depletes stem cells and over-activates WNT signaling in multiple myeloma [RNA-seq]

Project description:Dual inhibition of EZH1/2 depletes stem cells and over-activates WNT signaling in multiple myeloma [RNA-seq]

| PRJNA431630 | ENA

Dual inhibition of EZH1/2 depletes stem cells and over-activates WNT signaling in multiple myeloma

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-01-25 | GSE109675 | GEO

Polycomb Protein Ezh1 Promotes RNA Polymerase II Elongation

Project description:Polycomb group (PcG) proteins initiate the formation of repressed chromatin domains and regulate developmental gene expression. A mammalian PcG protein, Enhancer of Zeste homolog 2 (Ezh2), triggers transcriptional repression by catalyzing the addition of methyl groups onto lysine-27 of histone H3 (H3K27me2/3)1. This action facilitates the binding of other PcG proteins to histone H3 and compaction of chromatin. Interestingly, there exists a paralog of Ezh2, termed Ezh1, whose primary function remains unclear. Here, we provide evidence for genome-wide association of Ezh1 with active epigenetic marks, RNA polymerase II (PolII) and mRNA production. Ezh1 depletion reduced global PolII occupancy within gene bodies and resulted in delayed transcriptional activation during differentiation of skeletal muscle cells. Conversely, ectopic expression of wild-type Ezh1 led to premature gene activation and rescued PolII-elongation defects in Ezh1-depleted cells. Collectively, these findings reveal an unanticipated role of a PcG protein in promoting mRNA transcription. Examination of 3 different histone modifications, 3 modified forms of RNA polymerase II, Ezh1, Ezh2 and mRNA levels in a skeletal muscle cells at various developmental stages.

2011-11-23 | E-GEOD-25549 | biostudies-arrayexpress

The quantitative analysis of transcriptomes derived from malignant rhabdoid tumor cells treated with EZH1/2 dual inhibitor or EZH2 selective inhibitor

Project description:We found that both EZH1 and EZH2 contributes to cell growth and H3K27 methylation, and EZH1/2 dual inhibitors induce growth inhibition in malignant rhabdoid tumor (MRT). To investigate the molecular mechanism underlying the growth inhibition of EZH inhibitors in MRT cells, we performed RNA-sequencing analysis and compared differentially expressed genes between A204.1 cells treated with EZH1/2 dual inhibitor DS-3201b or EZH2 selective inhibitor EPZ-6438.

2022-09-01 | GSE205086 | GEO

An Ezh2 and Ezh1 dual inhibitor, UNC1999, re-shapes the landscape of H3K27me3 versus H3K27ac in MLL-AF9-transformed murine leukemia

Project description:Ezh2 and EZH1 are histone H3 lysine 27 (H3K27)-specific methyltransferases. Their hyperactive mutations and overexpression were found in cancer including various hematological malignancies. UNC1999 is a highly selective inhibitor for both enzymes. It suppresses H3K27 tri- and di-methylation globally and inhibits growth of MLL-rearranged acute leukemia. Here we performed ChIP-Seq to profile how UNC1999 affects distribution of H3K27me3 and its antagonizing H3K27ac in MLL-AF9-immortalized leukemia cells. We also performed ChIP-seq of SUZ12, an essential common cofactor of EZH2 and EZH1 following compound treatments. We treated MLL-AF9 transformed murine leukemia cells with DMSO, UNC1999 or UNC2400 (an inactive analog compound of UNC1999). Cells were then collected and used for ChIP-Sequencing of Input, H3K27me3, SUZ12, and H3K27ac.

2014-10-30 | E-GEOD-62437 | biostudies-arrayexpress

Expression data from LSK cells from mice with knock-out of Ezh1 versus LSK control

Project description:Ezh1 is a protein member of PRC2. Ezh1 has been described as a functional repressor gene, such as its homologous Ezh2. We are investigating the role of Ezh1 in hematopoietic stem cells, aging, self-renewal and differentiation. We used microarrays to detail the global program of gene expression in LSK cells from mice with knocked-down expression of Ezh1. LSK cells from EZH1 knockout and control mice were marked and isolated by fluorescence-activated cell sorting. 2 replicates each.

2012-03-06 | E-GEOD-36288 | biostudies-arrayexpress

Polycomb Protein Ezh1 Promotes RNA Polymerase II Elongation

2011-11-23 | GSE25549 | GEO

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