2024-03-29T00:05:51Z
https://u-ryukyu.repo.nii.ac.jp/oai
oai:u-ryukyu.repo.nii.ac.jp:02012376
2023-08-03T05:31:09Z
1642838163960:1642838338003
1642838403551:1642838407795
Targeting Excessive EZH1 and EZH2 Activities for Abnormal Histone Methylation and Transcription Network in Malignant Lymphomas
Yamagishi, Makoto
Hori, Makoto
Fujikawa, Dai
Ohsugi, Takeo
Honma, Daisuke
Adachi, Nobuaki
Katano, Harutaka
Hishima, Tsunekazu
Kobayashi, Seiichiro
Nakano, Kazumi
Nakashima, Makoto
Iwanaga, Masako
Utsunomiya, Atae
Tanaka, Yuetsu
Okada, Seiji
Tsukasaki, Kunihiro
Tobinai, Kensei
Araki, Kazushi
Watanabe, Toshiki
Uchimaru, Kaoru
Although global H3K27me3 reprogramming is a hallmark of cancer, no effective therapeutic strategy for H3K27me3-high malignancies harboring EZH2(WT/WT) has yet been established. We explore epigenome and transcriptome in EZH2(WT/WT) and EZH2(WT/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.
論文
http://purl.org/coar/resource_type/c_6501
Cell Press
2019-11-19
VoR
http://hdl.handle.net/20.500.12000/45873
2211-1247
Cell reports
8
29
2337
2321
eng
https://doi.org/10.1016/j.celrep.2019.10.083
https://doi.org/10.1016/j.celrep.2019.10.083
open access
Creative Commons Attribution-NonCommercial-NoDerivatives 4.0
https://creativecommons.org/licenses/by-nc-nd/4.0/