Histone-lysine N-methyltransferase EZH2 (EZH2) and Histone-lysine N-methyltransferase EZH1 (EZH1) (EZH2/EZH1)

Histone-lysine N-methyltransferase EZH2 (EZH2) and its paralog Histone-lysine N-methyltransferase EZH1 (EZH1) are the catalytic subunits of the Polycomb Repressive Complex 2 (PRC2), which mediates gene silencing through the tri-methylation of histone H3 at lysine 27 (H3K27me3) (UniProt Q15910, Q92800). This epigenetic mark is essential for regulating cell differentiation and maintaining stem cell identity by compacting chromatin and repressing transcription (PubMed: 22927404). In many malignancies, such as follicular lymphoma and epithelioid sarcoma, EZH2 is frequently overexpressed or mutated, leading to the pathological silencing of tumor suppressor genes (PubMed: 32066514). While tazemetostat is a potent and selective inhibitor of EZH2, EZH1 can often compensate for the loss of EZH2 activity, potentially leading to therapeutic resistance; thus, dual inhibition of both homologs is an area of active clinical interest (PubMed: 26030134). Tazemetostat binds to the SET domain of these enzymes to block their methyltransferase activity, thereby restoring the expression of genes that promote cell cycle arrest and apoptosis (FDA: Tazverik Prescribing Information).

Other names

Enhancer of zeste homolog 2Enhancer of zeste homolog 1KMT6AKMT6BENX-1ENX-2PRC2 catalytic subunits

Tazemetostat and related inhibitors act by competitively binding to the S-adenosyl-L-methionine (SAM) binding site within the SET domain of EZH2 and EZH1. This prevents the transfer of methyl groups to the lysine 27 residue of histone H3, thereby reducing H3K27me3 levels and reversing the epigenetic silencing of tumor suppressor genes (PubMed: 22927404, FDA: Tazverik Label).