Enhancer of zeste homolog 1 and 2 (EZH1/2)

Enhancer of zeste homolog 1 (EZH1) and 2 (EZH2) are paralogous histone methyltransferases that serve as the catalytic subunits of the Polycomb Repressive Complex 2 (PRC2). These enzymes are responsible for the mono-, di-, and tri-methylation of histone H3 at lysine 27 (H3K27), a critical epigenetic modification that promotes chromatin compaction and the transcriptional silencing of target genes involved in cell fate and differentiation. While EZH2 is the primary catalytic driver in rapidly proliferating cells, EZH1 often maintains H3K27 methylation in non-proliferating cells and can compensate for EZH2 loss, which frequently leads to resistance against selective EZH2 inhibitors. Overexpression or gain-of-function mutations in EZH1/2 are strongly associated with various malignancies, particularly hematological cancers such as T-cell and B-cell lymphomas, where they silence tumor suppressor genes to drive oncogenesis. Dual EZH1/2 inhibitors, such as the approved drug valemetostat, are designed to achieve more comprehensive suppression of H3K27me3 by blocking both paralogs, thereby overcoming compensatory mechanisms and providing a more potent therapeutic effect in relapsed or refractory cancers.

Other names

EZH1EZH2ENX-1ENX-2KMT6KMT6AKMT6BPolycomb repressive complex 2 catalytic subunit

Inhibition of histone H3 lysine 27 (H3K27) methyltransferase activity by competing with S-adenosyl-L-methionine (SAM) for the SET domain, leading to the depletion of H3K27me3 marks and the reactivation of silenced tumor suppressor genes.