Abstract
Although global H3K27me3 reprogramming is a hallmark of cancer, no effective therapeutic strategy for H3K27me3-high malignancies harboring EZH2WT/WT has yet been established. We explore epigenome and transcriptome in EZH2WT/WT and EZH2WT/Mu aggressive lymphomas and show that mutual interference and compensatory function of co-expressed EZH1 and EZH2 rearrange their own genome-wide distribution, thereby establishing restricted chromatin and gene expression signatures. Direct comparison of leading compounds introduces potency and a mechanism of action of the EZH1/2 dual inhibitor (valemetostat). The synthetic lethality is observed in all lymphoma models and primary adult T cell leukemia-lymphoma (ATL) cells. Opposing actions of EZH1/2-polycomb and SWI/SNF complexes are required for facultative heterochromatin formation. Inactivation of chromatin-associated genes (ARID1A, SMARCA4/BRG1, SMARCB1/SNF5, KDM6A/UTX, BAP1, KMT2D/MLL2) and oncovirus infection (HTLV-1, EBV) trigger EZH1/2 perturbation and H3K27me3 deposition. Our study provides the mechanism-based rationale for chemical dual targeting of EZH1/2 in cancer epigenome.
Keywords:
EZH1; EZH2; H3K27me3; HTLV-1; adult T cell leukemia-lymphoma (ATL); epigenetic drug; malignant lymphoma; polycomb.
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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DNA Helicases / genetics
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DNA Helicases / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Enhancer of Zeste Homolog 2 Protein / genetics
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Enhancer of Zeste Homolog 2 Protein / metabolism*
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Epigenome / genetics
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Herpesvirus 4, Human / pathogenicity
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Histone Demethylases / genetics
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Histone Demethylases / metabolism
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Histones / genetics
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Histones / metabolism*
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Human T-lymphotropic virus 1 / pathogenicity
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Humans
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Lymphoma / genetics*
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Lymphoma / metabolism*
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Methylation
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Polycomb Repressive Complex 2 / genetics
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Polycomb Repressive Complex 2 / metabolism*
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Retroviridae / pathogenicity
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SMARCB1 Protein / genetics
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SMARCB1 Protein / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Tumor Cells, Cultured
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
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Ubiquitin Thiolesterase / genetics
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Ubiquitin Thiolesterase / metabolism
Substances
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ARID1A protein, human
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BAP1 protein, human
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DNA-Binding Proteins
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Histones
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KMT2D protein, human
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Neoplasm Proteins
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Nuclear Proteins
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SMARCB1 Protein
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SMARCB1 protein, human
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Transcription Factors
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Tumor Suppressor Proteins
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Histone Demethylases
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KDM6A protein, human
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EZH1 protein, human
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EZH2 protein, human
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Enhancer of Zeste Homolog 2 Protein
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Polycomb Repressive Complex 2
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Ubiquitin Thiolesterase
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SMARCA4 protein, human
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DNA Helicases