Targeting Excessive EZH1 and EZH2 Activities for Abnormal Histone Methylation and Transcription Network in Malignant Lymphomas

Publication date: 19 November 2019Source: Cell Reports, Volume 29, Issue 8Author(s): Makoto Yamagishi, Makoto Hori, Dai Fujikawa, Takeo Ohsugi, Daisuke Honma, Nobuaki Adachi, Harutaka Katano, Tsunekazu Hishima, Seiichiro Kobayashi, Kazumi Nakano, Makoto Nakashima, Masako Iwanaga, Atae Utsunomiya, Yuetsu Tanaka, Seiji Okada, Kunihiro Tsukasaki, Kensei Tobinai, Kazushi Araki, Toshiki Watanabe, Kaoru UchimaruSummaryAlthough 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 ...
Source: Cell Reports - Category: Cytology Source Type: research