Polycomb repressive complex 2 (PRC2) (PRC2)

Polycomb repressive complex 2 (PRC2) is a multi-subunit epigenetic regulator responsible for the mono-, di-, and tri-methylation of histone H3 at lysine 27 (H3K27), a modification that leads to chromatin compaction and transcriptional silencing [1, 3, 6]. The core complex consists of the catalytic subunit EZH2 (or EZH1), and the structural/regulatory subunits EED and SUZ12 [1, 13]. PRC2 plays a fundamental role in maintaining stem cell identity, controlling cellular differentiation, and regulating developmental genes like Hox genes [3, 4, 13]. Dysregulation of PRC2, through either overexpression or gain-of-function mutations, is a common driver in various malignancies, including lymphomas and sarcomas, where it silences tumor suppressor genes [7, 9, 13]. Conversely, loss-of-function mutations are associated with overgrowth syndromes like Weaver syndrome and certain myeloid malignancies [4, 10]. Therapeutic targeting of PRC2 primarily involves small-molecule inhibitors of EZH2 or allosteric inhibitors of EED, aimed at restoring the expression of silenced genes and inducing cell differentiation or apoptosis in cancer cells [7, 8, 13].

Other names

PRC2Polycomb repressive complex 2EED-EZH2-SUZ12 complexH3K27 methyltransferase complex

Inhibition of the methyltransferase activity of the EZH2 subunit or allosteric inhibition via the EED subunit to prevent H3K27 trimethylation and restore gene expression [7, 8, 11].