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.
Makoto Yamagishi  1 ,  Makoto Hori  2 ,  Dai Fujikawa  3 ,  Takeo Ohsugi  4 ,  Daisuke Honma  5 ,  Nobuaki Adachi  6 ,  Harutaka Katano  7 ,  Tsunekazu Hishima  8 ,  Seiichiro Kobayashi  9 ,  Kazumi Nakano  2 ,  Makoto Nakashima  2 ,  Masako Iwanaga  10 ,  Atae Utsunomiya  11 ,  Yuetsu Tanaka  12 ,  Seiji Okada  13 ,  Kunihiro Tsukasaki  14 ,  Kensei Tobinai  15 ,  Kazushi Araki  16 ,  Toshiki Watanabe  17 ,  Kaoru Uchimaru  18
Affiliations
  • 1. Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan. Electronic address: [email protected].
  • 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: [email protected].
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 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 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.
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