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

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 Uchimaru

doi:10.1016/j.celrep.2019.10.083

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

Cell Rep. 2019 Nov 19;29(8):2321-2337.e7. doi: 10.1016/j.celrep.2019.10.083.

Authors

Makoto Yamagishi¹, Makoto Hori², Dai Fujikawa³, Takeo Ohsugi⁴, Daisuke Honma⁵, Nobuaki Adachi⁶, Harutaka Katano⁷, Tsunekazu Hishima⁸, Seiichiro Kobayashi⁹, Kazumi Nakano², Makoto Nakashima², Masako Iwanaga¹⁰, Atae Utsunomiya¹¹, Yuetsu Tanaka¹², Seiji Okada¹³, Kunihiro Tsukasaki¹⁴, Kensei Tobinai¹⁵, Kazushi Araki¹⁶, Toshiki Watanabe¹⁷, Kaoru Uchimaru¹⁸

Affiliations

¹ Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan. Electronic address: myamagishi@edu.k.u-tokyo.ac.jp.
² Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
³ Animal Models and Retroviral Vaccines Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
⁴ Department of Laboratory Animal Science, School of Veterinary Medicine, Rakuno Gakuen University, Hokkaido, Japan.
⁵ Oncology Laboratories, Daiichi Sankyo, Co., Tokyo, Japan.
⁶ Biomarker Department, Daiichi Sankyo, Co., Tokyo, Japan.
⁷ Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
⁸ Department of Pathology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.
⁹ Division of Molecular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
¹⁰ Department of Clinical Epidemiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
¹¹ Department of Hematology, Imamura General Hospital, Kagoshima, Japan.
¹² Graduate School and Faculty of Medicine, University of the Ryukyus, Okinawa, Japan.
¹³ Joint Research Center for Human Retrovirus Infection, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
¹⁴ Department of Hematology, International Medical Center, Saitama Medical University, Saitama, Japan.
¹⁵ Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.
¹⁶ Oncology Clinical Development Department, Daiichi Sankyo Co., Tokyo, Japan.
¹⁷ Future Center Initiative, The University of Tokyo, Tokyo, Japan.
¹⁸ Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan. Electronic address: uchimaru@cbms.k.u-tokyo.ac.jp.

PMID: 31747604
DOI: 10.1016/j.celrep.2019.10.083

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.

Keywords: EZH1; EZH2; H3K27me3; HTLV-1; adult T cell leukemia-lymphoma (ATL); epigenetic drug; malignant lymphoma; polycomb.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

ARID1A protein, human
BAP1 protein, human
DNA-Binding Proteins
Histones
KMT2D protein, human
Neoplasm Proteins
Nuclear Proteins
SMARCB1 Protein
SMARCB1 protein, human
Transcription Factors
Tumor Suppressor Proteins
Histone Demethylases
KDM6A protein, human
EZH1 protein, human
EZH2 protein, human
Enhancer of Zeste Homolog 2 Protein
Polycomb Repressive Complex 2
Ubiquitin Thiolesterase
SMARCA4 protein, human
DNA Helicases