see also:

• neoplasia / cancer / tumours
• scleroderma
• asthma
• wikipedia: EZH2

• 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

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

• these may have a role in treating:
  • neoplasia / cancer / tumours
  • scleroderma
    • epigenetic dysregulation and overexpression of LRRC16A appears to explain Ezh2-mediated fibroblast migration in scleroderma ²⁾
  • asthma ³⁾
    • 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.