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Genome-wide chromatin accessibility change after PRC2 inhibition by MAK683 treatment

ABSTRACT: The methyltransferase Polycomb Repressive Complex 2 (PRC2), composed of EZH2, SUZ12, and EED subunits, is associated with transcriptional repression via tri-methylation of histone H3 on lysine 27 residue (H3K27me3). PRC2 is a validated drug target, as the EZH2 gain-of-function mutations identified in patient samples drive tumorigenesis. PRC2 inhibitors have been discovered and demonstrated anti-cancer efficacy in clinic. However, their pharmacological mechanisms are poorly understood. MAK683 is a potent EED inhibitor in clinical development. The overall goal of our study is to understand the molecular events leading to tumor regression after PRC2 inhibition. Our study revealed that multiple senescence-associated secretory phenotype (SASP) genes, such as Gata4, Mmp2/10, Itga2 and Gbp1, are derepressed upon PRC2 inhibition and contribute to decreased Ki67+, ECM reorganization, inflammation and tumor regression even in Cdkn2a/p16 knockout tumor.

ORGANISM(S): Homo sapiens

PROVIDER: GSE183602 | GEO | 2022/03/09

REPOSITORIES: GEO

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H3K27me3 and H3K4me3 ChIP-seq on DMSO or MAK683 treated cancer cell

Project description:The methyltransferase Polycomb Repressive Complex 2 (PRC2), composed of EZH2, SUZ12, and EED subunits, is associated with transcriptional repression via tri-methylation of histone H3 on lysine 27 residue (H3K27me3). PRC2 is a validated drug target, as the EZH2 gain-of-function mutations identified in patient samples drive tumorigenesis. PRC2 inhibitors have been discovered and demonstrated anti-cancer efficacy in clinic. However, their pharmacological mechanisms are poorly understood. MAK683 is a potent EED inhibitor in clinical development. The overall goal of our study is to understand the molecular events leading to tumor regression after PRC2 inhibition. Our study revealed that multiple senescence-associated secretory phenotype (SASP) genes, such as Gata4, Mmp2/10, Itga2 and Gbp1, are derepressed upon PRC2 inhibition and contribute to decreased Ki67+, ECM reorganization, inflammation and tumor regression even in Cdkn2a/p16 knockout tumor.

2022-03-09 | GSE183601 | GEO

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Project description:The methyltransferase Polycomb Repressive Complex 2 (PRC2), composed of EZH2, SUZ12, and EED subunits, is associated with transcriptional repression via tri-methylation of histone H3 on lysine 27 residue (H3K27me3). PRC2 is a validated drug target, as the EZH2 gain-of-function mutations identified in patient samples drive tumorigenesis. PRC2 inhibitors have been discovered and demonstrated anti-cancer efficacy in clinic. However, their pharmacological mechanisms are poorly understood. MAK683 is a potent EED inhibitor in clinical development. The overall goal of our study is to understand the molecular events leading to tumor regression after PRC2 inhibition. Our study revealed that BMP-ACVR1 signaling pathway as a critical component for the anti-lymphoma efficacy of PRC2 inhibitor.

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RNA-seq on DMSO or MAK683 treated cancer cells and xenograft tumor samples

Project description:The methyltransferase Polycomb Repressive Complex 2 (PRC2), composed of EZH2, SUZ12, and EED subunits, is associated with transcriptional repression via tri-methylation of histone H3 on lysine 27 residue (H3K27me3). PRC2 is a validated drug target, as the EZH2 gain-of-function mutations identified in patient samples drive tumorigenesis. PRC2 inhibitors have been discovered and demonstrated anti-cancer efficacy in clinic. However, their pharmacological mechanisms are poorly understood. MAK683 is a potent EED inhibitor in clinical development. The overall goal of our study is to understand the molecular events leading to tumor regression after PRC2 inhibition. Our study revealed that BMP-ACVR1 signaling pathway as a critical component for the anti-lymphoma efficacy of PRC2 inhibitor.

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Project description:The methyltransferase Polycomb Repressive Complex 2 (PRC2), composed of EZH2, SUZ12, and EED subunits, is associated with transcriptional repression via tri-methylation of histone H3 on lysine 27 residue (H3K27me3). PRC2 is a validated drug target, as the EZH2 gain-of-function mutations identified in patient samples drive tumorigenesis. PRC2 inhibitors have been discovered and demonstrated anti-cancer efficacy in clinic. However, their pharmacological mechanisms are poorly understood. MAK683 is a potent EED inhibitor in clinical development. The overall goal of our study is to understand the molecular events leading to tumor regression after PRC2 inhibition. Our study revealed that BMP-ACVR1 signaling pathway as a critical component for the anti-lymphoma efficacy of PRC2 inhibitor.

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Project description:Polycomb repressive complex (PRC) 2, containing minimally EZH2, EED and Suz12, is the H3 lysine 27 methyltransferase playing pivotal roles in transcriptional regulation. EZH2 is the catalytic subunit, and H3K27me3 activates PRC2 through binding EED to propagate the repressive mark. Cofactor SAM-competitive (SAM-C) PRC2 inhibitors (PRC2is) have been discovered to treat lymphoma and rhabdoid tumors. Here we report the discovery of EED226, a potent and selective PRC2i directly binding to the H3K27me3 pocket of EED. Upon binding, EED226 induces conformational change in EED protein. Interestingly, it inhibits both the basal and the H3K27me3-stimulated PRC2 activities. Furthermore, EED226 selectively pulled down the endogenous PRC2 complex from human cell lysates, specifically modulates H3K27 methylation and target genes similarly as SAM-C PRC2 inhibitors, and effectively regresses human lymphoma xenograft tumor in mouse. More importantly, EED226 potently inhibits the SAM-C inhibitor-resistant PRC2 and synergizes with SAM-C PRC2i in cell proliferation blocking. Together, EED226 is an inhibitor of PRC2 with a novel mechanism and represent a potential complementary strategy for PRC2-targeted cancer therapy.

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