Enhancer of zeste homolog 2 (EZH2) (EZH2)

Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that serves as the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) [UniProt: P35226]. It primarily functions by methylating Lysine 27 of Histone H3 (H3K27), a modification that leads to chromatin condensation and transcriptional silencing of target genes [PubMed: 32103341]. This epigenetic regulation is vital for maintaining stem cell pluripotency and governing lineage specification during development. In many cancers, EZH2 is either overexpressed or harbors gain-of-function mutations, leading to the silencing of tumor suppressor genes and promoting tumor growth and survival [NCBI Gene: 2146]. Consequently, EZH2 has become a significant therapeutic target, particularly in hematologic malignancies and certain solid tumors like epithelioid sarcoma. Small-molecule inhibitors, such as the FDA-approved drug tazemetostat, target the SET domain of EZH2 to block its enzymatic activity and restore normal gene expression patterns [FDA: Tazverik Label].

Other names

ENX-1KMT6KMT6ALysine N-methyltransferase 6WVSWVS2Histone-lysine N-methyltransferase EZH2

EZH2 inhibitors act as S-adenosyl-L-methionine (SAM) competitive inhibitors that bind to the catalytic SET domain of the EZH2 enzyme [PubMed: 25135958]. This binding prevents the transfer of methyl groups to the H3K27 residue, effectively reducing global H3K27me3 levels and reversing the epigenetic repression of genes involved in cell cycle control and differentiation [PubMed: 32103341].