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Title Targeting Excessive EZH1 and EZH2 Activities for Abnormal Histone Methylation and Transcription Network in Malignant Lymph Targeting Excessive EZH1 and EZH2 Activities for Abnormal Title 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; Author(s) Nakashima, Makoto; Iwanaga, Masako; Utsunomiya, Atae; Tanaka, Yuetsu; Okada, Seiji; Tsukasaki, Kunihiro; Tobinai, Kensei; Araki, Kazushi; Watanabe, Toshiki; Uchimaru, Kaoru Citation Cell reports, 29(8): 2321-2337 Issue Date 2019-11-19 URL http://hdl.handle.net/20.500.12000/45873 Creative Commons Attribution-NonCommercial- Rights NoDerivatives 4.0 Article Targeting Excessive EZH1 and EZH2 Activities for Abnormal Histone Methylation and Transcription Network in Malignant Lymphomas Graphical Abstract Authors Makoto Yamagishi, Makoto Hori, Dai Fujikawa, ..., Kazushi Araki, Toshiki Watanabe, Kaoru Uchimaru Correspondence [email protected] (M.Y.), [email protected] (K.U.) In Brief A mechanism-based, effective strategy for controlling oncogenic H3K27me3 remains an open question. Yamagishi et al. provide the scientific rationale for dual targeting of EZH1+EZH2 in malignancies overexpressing EZH2, such as ATL, PTCL, and DLBCL, or harboring mutations in histone-modifying genes, as well as in pre-cancerous cells epigenomically perturbed by oncovirus infection. Highlights d Lymphoma transcriptome is under control of global H3K27me3 accumulation WT/WT d EZH1 and EZH2 are druggable targets in EZH2 and EZH2WT/Mu malignancies d Inactivation of chromatin-associated genes triggers EZH1/2 perturbation d Targeting epigenome for pre-cancerous states is achieved by EZH1/2 inhibition Yamagishi et al., 2019, Cell Reports 29, 2321–2337 November 19, 2019 ª 2019 The Author(s). https://doi.org/10.1016/j.celrep.2019.10.083 Cell Reports Article Targeting Excessive EZH1 and EZH2 Activities for Abnormal Histone Methylation and Transcription Network in Malignant Lymphomas Makoto Yamagishi,1,17,* Makoto Hori,1 Dai Fujikawa,2 Takeo Ohsugi,3 Daisuke Honma,4 Nobuaki Adachi,5 Harutaka Katano,6 Tsunekazu Hishima,7 Seiichiro Kobayashi,8 Kazumi Nakano,1 Makoto Nakashima,1 Masako Iwanaga,9 Atae Utsunomiya,10 Yuetsu Tanaka,11 Seiji Okada,12 Kunihiro Tsukasaki,13 Kensei Tobinai,14 Kazushi Araki,15 Toshiki Watanabe,16 and Kaoru Uchimaru1,* 1Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan 2Animal Models and Retroviral Vaccines Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA 3Department of Laboratory Animal Science, School of Veterinary Medicine, Rakuno Gakuen University, Hokkaido, Japan 4Oncology Laboratories, Daiichi Sankyo, Co., Tokyo, Japan 5Biomarker Department, Daiichi Sankyo, Co., Tokyo, Japan 6Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan 7Department of Pathology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan 8Division of Molecular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan 9Department of Clinical Epidemiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan 10Department of Hematology, Imamura General Hospital, Kagoshima, Japan 11Graduate School and Faculty of Medicine, University of the Ryukyus, Okinawa, Japan 12Joint Research Center for Human Retrovirus Infection, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan 13Department of Hematology, International Medical Center, Saitama Medical University, Saitama, Japan 14Department of Hematology, National Cancer Center Hospital, Tokyo, Japan 15Oncology Clinical Development Department, Daiichi Sankyo Co., Tokyo, Japan 16Future Center Initiative, The University of Tokyo, Tokyo, Japan 17Lead Contact *Correspondence: [email protected] (M.Y.), [email protected] (K.U.) https://doi.org/10.1016/j.celrep.2019.10.083 SUMMARY for chemical dual targeting of EZH1/2 in cancer epi- genome. Although global H3K27me3 reprogramming is a hall- mark of cancer, no effective therapeutic strategy for H3K27me3-high malignancies harboring EZH2WT/WT INTRODUCTION has yet been established. We explore epigenome and transcriptome in EZH2WT/WT and EZH2WT/Mu Histone H3 regulation, particularly H3 lysine 27 trimethylation aggressive lymphomas and show that mutual inter- (H3K27me3), is a central process for chromatin condensation and gene silencing. The suppressive histone mark is catalyzed ference and compensatory function of co-ex- by polycomb repressive complex 2 (PRC2), which includes pressed EZH1 and EZH2 rearrange their own either enhancer of zeste homolog 1 (EZH1) or EZH2 as an enzy- genome-wide distribution, thereby establishing matically active core subunit, as well as other components, such restricted chromatin and gene expression signa- as EED and SUZ12. A heterozygous gain-of-function (GoF) mu- tures. Direct comparison of leading compounds in- tation of EZH2 has been observed in certain lymphoma types, troduces potency and a mechanism of action of contributing to increased H3K27me3 (Morin et al., 2010; Be´ gue- the EZH1/2 dual inhibitor (valemetostat). The syn- lin et al., 2013). In contrast, many other cancer types, including thetic lethality is observed in all lymphoma models the majority of malignant lymphomas and various solid tumors, and primary adult T cell leukemia-lymphoma (ATL) also show overexpression of EZH2 and global H3K27me3 accu- cells. Opposing actions of EZH1/2-polycomb and mulation irrespective of EZH2 gene mutation (Comet et al., 2016; SWI/SNF complexes are required for facultative het- Fujikawa et al., 2016). Epigenomic studies, particularly those ad- dressing chromatin and transcription regulation, have demon- erochromatin formation. Inactivation of chromatin- ARID1A SMARCA4/BRG1 strated that inappropriate H3K27me3 deposition is a critical associated genes ( , , determinant of the abnormal transcriptome of various cancers SMARCB1/SNF5 KDM6A/UTX BAP1 KMT2D/ , , , (Pfister and Ashworth, 2017; Yamagishi and Uchimaru, 2017). MLL2) and oncovirus infection (HTLV-1, EBV) trigger Because H3K27me3 is an enzymatic product, this reversible EZH1/2 perturbation and H3K27me3 deposition. property provides a good foundation for the development Our study provides the mechanism-based rationale of epigenetic drugs. Several small compounds have been Cell Reports 29, 2321–2337, November 19, 2019 ª 2019 The Author(s). 2321 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). ABC DE F G HI J K L Figure 1. EZH1- and EZH2-Dependent H3K27me3 Accumulation (A) ATL cell lines were transduced with shRNA lentivirus vectors. Venus-positive population transduced with shRNA series are plotted (representative data, n = 2 biological replicates). (B) EZH1 (x axis) and EZH2 (y axis) levels in various normal cell types. (legend continued on next page) 2322 Cell Reports 29, 2321–2337, November 19, 2019 developed as potential EZH2 inhibitors (McCabe et al., 2012; H3K27me3-mediated gene repression (Fujikawa et al., 2016) Knutson et al., 2013; Qi et al., 2012; Bradley et al., 2014), as was found to be correlated with poor prognostic markers (Iwa- well as EZH1/2 dual inhibitors (Xu et al., 2015a; Honma et al., naga et al., 2010; Katsuya et al., 2012)(Figures S1A and S1B). 2017). The inhibitors of the methyltransferase activity diminish Global gene downregulation, including that of important genes the abundance of H3K27me3 and decrease the growth of cancer for leukemogenesis and also targets of genetic lesions (Kataoka cells harboring EZH2 GoF mutations. In addition, recent clinical et al., 2015), was associated with H3K27me3 accumulation study further reported the potential safety and efficacy of the (Figures S1C and S1D). H3K27me3 was acquired at originally un- EZH2 inhibitor against the EZH2 mutant B cell lymphomas (Ital- methylated promoters in ATL cells, suggesting neomorphic iano et al., 2018). However, these studies concurrently suggest functions of the polycomb family with EZH2WT/WT (Fujikawa that H3K27me3-high malignancies harboring EZH2WT/WT are et al., 2016)(Figure S1E). relatively tolerant to EZH2 inhibitors. Only two enzymes catalyze H3K27me3 in mammalian cells. EZH1- and EZH2-Dependent H3K27me3 Accumulation The importance of EZH1 in chromatin regulation has also been in ATL pointed out (Shen et al., 2008; Margueron et al., 2008). A cancer We tested the functional importance of PRC1/2 components us- panel assay in vitro and some in vivo models suggested that the ing short hairpin RNA (shRNA)-mediated gene knockdown (KD) EZH1/2 dual inhibitors have efficacy against several cancer screening in two ATL-derived cell lines. Selective reduction of types (Honma et al., 2017). However, the underlying mecha- proliferation was observed in the PRC-defective cells (Figures nisms of gene silencing and therapeutic efficacies of the epige- 1A and S2A). In particular, EZH1 and EZH2 were found to be netic drugs remain under discussion, because of a lack of data independently required for ATL cell proliferation (Figure S2B). representing the dynamic action of the corresponding histone RNA sequencing (RNA-seq) data (Kundaje et al., 2015) showed methyltransferases and other chromatin regulators. The func- that EZH1 and EZH2 genes were reciprocally regulated in phys- tional distribution and molecular dynamics of PRC2-EZH1 and iological states (Figures
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