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.

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.

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