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Loss-of-function mutations in the histone methyltransferase EZH2 promote chemotherapy resistance in AML

ABSTRACT: We report that loss of EZH2 provides leukaemia cells with a selective growth advantage, which mediates chemotherapy resistance. This resistance is conferred by up regulation of direct and indirect EZH2 target genes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE162623 | GEO | 2021/03/12

REPOSITORIES: GEO

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Full proteome analysis of WT and Ezh2-KO K562 cells

Project description:Chemotherapy resistance is the main impediment in the treatment of acute myeloid leukaemia (AML). Despite rapid advances, the various mechanisms that lead to resistance development remain to be defined in detail. Here we report that loss-of-function mutations (LOF) in the histone methyltransferase EZH2 have the potential to confer resistance against the chemotherapeutic agent cytarabine. We identify seven distinct EZH2 mutations leading to loss of H3K27 trimethylation via multiple mechanisms. Analysis of matched diagnosis and relapse samples reveal a heterogenous regulation of EZH2 and a loss of EZH2 in 50% of patients. We confirm that loss of EZH2 induces resistance against cytarabine in the cell lines HEK293T and K562 as well as in a patient-derived xenograft (PDX) model. Proteomics and transcriptomics analysis reveal that resistance is conferred by upregulation of multiple direct and indirect EZH2 target genes that are involved in apoptosis evasion, augmentation of proliferation and alteration of transmembrane transporter function. Our data indicates, that loss of EZH2 results in upregulation of its target genes, providing the cell with a selective growth advantage, which mediates chemotherapy resistance.

2021-03-12 | PXD023139 | Pride

Loss-of-function mutations in the histone methyltransferase EZH2 promote chemotherapy resistance in AML.

Project description: Not available

| S-EPMC7955088 | biostudies-literature

Loss-of-function mutations in the histone methyltransferase EZH2 promote chemotherapy resistance in AML

Project description:Loss-of-function mutations in the histone methyltransferase EZH2 promote chemotherapy resistance in AML

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Inactivation of the histone H3 K36 methyltransferase NSD1 confers resistance to EZH2 inhibition [ChIP-Seq]

Project description:Disruption of antagonism between SWI/SNF chromatin remodelers and Polycomb repressor complexes drives the formation of numerous cancer types. Recently, an inhibitor of Polycomb protein EZH2 was approved for treatment of sarcomas mutant in SWI/SNF subunit SMARCB1, but resistance occurs. Here we sought to identify additional contributors to SWI/SNF-Polycomb antagonism and potential resistance mechanisms. We performed CRISPR screens and found that NSD1 loss caused resistance to EZH2 inhibition. NSD1 loss reduced H3K36me2 and impaired transcriptional activation of targets inhibited by EZH2 or activated by SMARCB1. Further, inhibiting the H3K36me2 demethylase KDM2A restored EZH2 inhibition in cells lacking NSD1. Our results expand the mechanistic understanding of SWI/SNF and Polycomb interplay and identify NSD1 as key for coordinating this transcriptional control.

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Inactivation of the histone H3 K36 methyltransferase NSD1 confers resistance to EZH2 inhibition [RNA-Seq]

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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.

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Treatment of CML CD34+ cells with EZH2 inhibitor GSK343

Project description:Transcriptional profiling by array of CML CD34+ cells to understand the response of chronic myeloid leukaemia stem cells to an EZH2 inhibitor, GSK343.

2016-11-01 | E-MTAB-2893 | biostudies-arrayexpress

EZH2 depletion potentiates MYC degradation inhibiting neuroblastoma and small cell carcinoma tumor formation

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2022-02-17 | PXD029652 | Pride

Characterization of the EZH2-MMSET histone methyltransferase regulatory axis in cancer

Project description:This SuperSeries is composed of the following subset Series: GSE41651: Characterization of the EZH2-MMSET histone methyltransferase regulatory axis in cancer [expression] GSE41652: Characterization of the EZH2-MMSET histone methyltransferase regulatory axis in cancer [ChIP-seq] Refer to individual Series

2012-11-15 | E-GEOD-41653 | biostudies-arrayexpress

Characterization of the EZH2-MMSET histone methyltransferase regulatory axis in cancer [expression]

Project description:Histone methyltransferases (HMTases), as chromatin modifiers, regulate the transcriptomic landscape in normal development as well in diseases such as cancer. Here, we molecularly order two HMTases, EZH2 and MMSET that have established genetic links to oncogenesis. EZH2, which mediates histone H3K27 trimethylation and is associated with gene silencing, was shown to be coordinately expressed and function upstream of MMSET, which mediates H3K36 dimethylation and is associated with active transcription. We found that the EZH2-MMSET HMTase axis is coordinated by a microRNA network and that the oncogenic functions of EZH2 require MMSET activity. Together, these results suggest that the EZH2-MMSET HMTase axis coordinately functions as a master regulator of transcriptional repression, activation, and oncogenesis and may represent an attractive therapeutic target in cancer. LacZ control vs MMSET overexpression or MMSET DeltaSET overexpression in replicates

2012-11-15 | E-GEOD-41651 | biostudies-arrayexpress

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