HDAC2: a potential target for neurological diseases

Abstract

Oxidative stress affects diverse biological processes, including neuron homeostasis, survival and death. Most neurological disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and stroke, are associated with oxidative stress. It has been extensively investigated that FOXO3a participates in the oxidative stress-induced neuronal apoptosis. However, the function of FOXO3a complexes in oxidative stress processing remains unclear. Recently we identified FOXO3a forms complex with Histone deacetylase 1 (HDAC1) and HDAC2. Under oxidative stress stimuli, the physical interaction between FOXO3a and HDAC1 or HDAC2 was disrupted. Further neuronal apoptosis assay demonstrated that knockdown HDAC2, but not HDAC1, reduced oxidative stress-induced neuronal cell death. Mechanistically, HDAC2 is recruited onto p21 promoter by FOXO3a and deacetylates the surrounding histone at H4K16, hence regulates p21 expression, which inhibits neuronal apoptosis. In addition, we discovered that oxidative stress-mediated HDAC2 Serine 394 (S394) phosphorylation regulated FOXO3a-HDAC2 interaction. Our research suggests that HDAC2 might be therapeutic target for neuron apoptosis-related diseases, including cerebral ischemia and degenerative diseases.