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Title :Targeting Excessive EZH1 and EZH2 Activities for Abnormal Histone Methylation and Transcription Network in Malignant Lymphomas
Authors :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
Issue Date :19-Nov-2019
Abstract :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.
URL :https://doi.org/10.1016/j.celrep.2019.10.083
Type Local :雑誌掲載論文
ISSN :2211-1247
Publisher :Cell Press
URI :http://hdl.handle.net/20.500.12000/45873
Citation :Cell reports Vol.29 no.8 p.2321 -2337
Appears in Collections:Peer-reviewed Journal Articles (Faculty of Medicine)

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