Polycomb repressive complex 2 (PRC2) via Embryonic ectoderm development (EED) subunit (PRC2-EED)

The Polycomb repressive complex 2 (PRC2) is a critical epigenetic regulator responsible for the trimethylation of histone H3 at lysine 27 (H3K27me3), a modification that leads to transcriptional silencing of target genes [1, 3]. The Embryonic ectoderm development (EED) subunit is a core component of this complex that acts as both a scaffold and an allosteric activator [2, 5]. EED contains a WD40 repeat domain with a specific pocket that binds to pre-existing H3K27me3 marks, which in turn triggers a conformational change in the catalytic subunit EZH2 to enhance its methyltransferase activity [2, 15]. Dysregulation of PRC2, often through overexpression or gain-of-function mutations in EZH2, is linked to various malignancies, including B-cell lymphomas and solid tumors, where it silences tumor suppressor genes [1, 8]. Targeting the EED subunit offers a novel therapeutic strategy by allosterically inhibiting the entire complex, which can overcome resistance seen with traditional SAM-competitive EZH2 inhibitors [4, 25]. Several EED inhibitors, such as MAK683 and EED226, are currently in clinical and preclinical development for the treatment of advanced cancers [1, 12].

Other names

Embryonic ectoderm developmentEEDhEEDWD protein associating with integrin cytoplasmic tails 1WAIT-1Polycomb protein EED

Allosteric inhibition of the Polycomb repressive complex 2 (PRC2) by binding to the H3K27me3-binding pocket of the Embryonic ectoderm development (EED) subunit, which prevents allosteric activation of the catalytic subunit EZH2 and leads to a global reduction in H3K27me3 levels [1, 23].