RRC ID 58263
Author Yamagishi M, Hori M, Fujikawa D, Ohsugi T, Honma D, Adachi N, Katano H, Hishima T, Kobayashi S, Nakano K, Nakashima M, Iwanaga M, Utsunomiya A, Tanaka Y, Okada S, Tsukasaki K, Tobinai K, Araki K, Watanabe T, Uchimaru K.
Title Targeting Excessive EZH1 and EZH2 Activities for Abnormal Histone Methylation and Transcription Network in Malignant Lymphomas.
Journal Cell Rep
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.
Volume 29(8)
Pages 2321-2337.e7
Published 2019-11-19
DOI 10.1016/j.celrep.2019.10.083
PII S2211-1247(19)31405-6
PMID 31747604
MeSH Adult DNA Helicases / genetics DNA Helicases / metabolism DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism Enhancer of Zeste Homolog 2 Protein / genetics Enhancer of Zeste Homolog 2 Protein / metabolism* Epigenome / genetics Herpesvirus 4, Human / pathogenicity Histone Demethylases / genetics Histone Demethylases / metabolism Histones / genetics Histones / metabolism* Human T-lymphotropic virus 1 / pathogenicity Humans Lymphoma / genetics* Lymphoma / metabolism* Methylation Neoplasm Proteins / genetics Neoplasm Proteins / metabolism Nuclear Proteins / genetics Nuclear Proteins / metabolism Polycomb Repressive Complex 2 / genetics Polycomb Repressive Complex 2 / metabolism* Retroviridae / pathogenicity SMARCB1 Protein / genetics SMARCB1 Protein / metabolism Transcription Factors / genetics Transcription Factors / metabolism Tumor Cells, Cultured Tumor Suppressor Proteins / genetics Tumor Suppressor Proteins / metabolism Ubiquitin Thiolesterase / genetics Ubiquitin Thiolesterase / metabolism
IF 8.109
Times Cited 5
DNA material CS-RfA-EVBsd (RDB06090) pENTR4-H1 (RDB04395) pCAG-HIVgp (RDB04394) pCMV-VSV-G-RSV-Rev (RDB04393)
Human and Animal Cells ATN-1(RCB1440)