Histone deacetylase 2 (HDAC2) within the CoREST complex (HDAC2-CoREST)

Histone deacetylase 2 (HDAC2) is a Class I histone deacetylase that functions as a critical catalytic subunit within the CoREST (REST corepressor 1) complex, alongside the lysine-specific demethylase 1 (LSD1/KDM1A) and the scaffold protein RCOR1 (UniProt P35266; PubMed: 10759898). This multi-protein assembly acts as a master epigenetic regulator, coordinating the removal of activating histone marks—specifically acetyl groups via HDAC2 and methyl groups from H3K4 via LSD1—to maintain transcriptional repression (PubMed: 16079794). The HDAC2-CoREST complex is essential for neuronal development and the silencing of neuronal genes in non-neuronal tissues, but its dysregulation is implicated in various pathologies, including the progression of acute myeloid leukemia (AML), solid tumors, and cognitive impairment in Alzheimer's disease (PubMed: 22388814; PubMed: 29463893). In therapeutic contexts, HDAC2 is a major target for histone deacetylase inhibitors (HDACis), which aim to reverse repressive chromatin states and restore the expression of tumor suppressor genes or factors involved in synaptic plasticity. Recent drug development has focused on bifunctional inhibitors like Corin, which are specifically designed to target both the HDAC2 and LSD1 enzymatic sites within the CoREST complex to achieve synergistic therapeutic effects while potentially reducing off-target toxicity (PubMed: 29463893). Consequently, targeting HDAC2 within this specific complex represents a sophisticated approach to precision medicine in oncology and neurology (PubChem CID 134821491).

Other names

HDAC2Histone deacetylase 2RPD3CoREST complexREST corepressor 1 complexRCOR1-LSD1-HDAC2 complex

HDAC2 within the CoREST complex catalyzes the hydrolytic removal of acetyl groups from N-acetyl lysine residues on histones H3 and H4, leading to a condensed chromatin structure and transcriptional repression (UniProt P35266). When targeted by dual inhibitors like Corin, both the deacetylase activity of HDAC2 and the demethylase activity of the associated LSD1 are inhibited, leading to synergistic increases in H3K9 acetylation and H3K4 methylation (PubMed: 29463893).