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Ezh2 antagonists


  • Ezh = Enhancer of zeste homolog
  • Ezh2 is the is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) and a member of the SET domain family of lysine methyltransferases which function to add methyl groups to lysine side chains of substrate proteins.
  • Ezh2 is highly conserved through evolution in plants and animals
  • Ezh2's primary function is as a histone methyltransferase, to methylate Lys-27 on histone 3 (H3K27me) by transferring a methyl group from the cofactor S-adenosyl-L-methionine (SAM) and by catalyzing the trimethylation of H3K27 to form H3K27me3
  • methylation of histone proteins is a key component of epigenetic regulation of gene transcription.
    • specific genes that have been identified as targets of EZH2-mediated transcriptional repression include HOXA9, HOXC8, MYT1, CDKN2A and retinoic acid target genes
  • Ezh2 is also capable of methylating non-histone proteins
  • Ezh2 typically is not expressed in healthy adults
    • it is only found in actively dividing cells, like those active during fetal development
    • some bacterial infections may increase EZH2 levels and thus modify epigenetic regulation 1)
    • it is over-expressed in some cancers some of which have mutant forms of Ezh2
  • Ezh2 has key roles in:
    • development and cell differentiation
      • appears to be important for maintenance of normal cell differentiation in plants, insects, fish, and mammals
      • important in driving X-inactivation, the silencing of one X-chromosome in females during development
      • maybe involved in initiating heterochromatin formation which is required for proper chromosome segregation during cell division
    • the immune system
      • EZH2 has been identified as an essential protein involved in development and differentiation of B-cells and T-cells.
      • Ezh2 appears to be critical to the immune system’s ability to drive inflammation in response to allergens
    • possible role in some cancers
      • EZH2 helps cancer cells divide and proliferate
      • when EZH2 is over-expressed it may turn off tumour suppressor genes
      • EZH2 is found in higher than normal amounts in various cancers such as breast, prostate, bladder, uterine, and renal cancers, as well as melanoma and lymphoma.
      • H3K27me3 is involved in suppressing genes that promote differentiation, thus maintaining an undifferentiated state of B- and T-cells and playing an important role in regulating hematopoiesis

Ezh2 gene mutations

  • Weaver syndrome
    • a rare disorder characterized by advanced bone age, macrocephaly, and hypertelorism.
    • due to disruption of normal EZH2 function

Ezh2 antagonists / inhibitors

  • these may have a role in treating:
      • epigenetic dysregulation and overexpression of LRRC16A appears to explain Ezh2-mediated fibroblast migration in scleroderma 2)
      • seems to switch off the inflammatory component in asthmatic patients 4)
      • however, EZH2 appears to also be a central regulator of iNKT pathogenicity and suppresses the ability of iNKT cells to induce asthma-like pathology. 5)
  • inhibitors of the hydrolysis of S-adenosyl-L-homocysteine (SAH)
    • these are non-specific and inhibit DNA methyltransferases in general (as well as EZH2)
  • S-adenosylmethionine (SAM) competitive inhibitors
    • Sinefungin is non-selective
    • tazemetostat (EPZ-6438)
    • EPZ005687 is 50x more selective for EZH2 compared to EZH1.
    • GSK126 is 150x more selective for EZH2 compared to EZH1.
ezh2antagonists.txt · Last modified: 2019/05/17 09:39 by gary1