| HDAC5 is a class IIa histone deacetylase that acts as a signal‑regulated transcriptional corepressor, linking extracellular and intracellular cues to chromatin deacetylation and repression of defined gene programs in muscle, endothelium, heart, brain, and cancer. The protein contains an N‑terminal regulatory region with multiple serine phosphorylation sites, 14‑3‑3‑binding motifs, and interaction regions for transcription factors such as MEF2, GATA1, and SATB1, and a C‑terminal catalytic domain with the conserved HDAC fold that deacetylates lysines in the N‑terminal tails of core histones when assembled into multiprotein complexes with HDAC3 and NCOR/SMRT. HDAC5 tethered to MEF2 or other transcription factors at target promoters maintains low histone acetylation, a compact chromatin state, and reduced transcription of genes involved in myogenesis, angiogenesis, inflammatory responses, and oncogenic programs, and changes in its localization or modification status rapidly alter the expression of these sets. Phosphorylation of HDAC5 at key serines by kinases such as CaMK, PKD, AMPK, SIK1, and GRK5 creates high‑affinity docking sites for 14‑3‑3 proteins and triggers CRM1‑dependent nuclear export, relieving repression of MEF2‑dependent and other target genes and allowing activation of muscle differentiation and hypertrophic gene expression in response to calcium, adrenergic, and metabolic signals. Dephosphorylation by PP2A–B55α complexes or impaired phosphorylation promotes nuclear retention and sustained repression, and these opposing phosphorylation–dephosphorylation cycles integrate neurohormonal and mechanical inputs into dynamic control of HDAC5 nuclear occupancy in cardiomyocytes and vascular cells. In endothelial cells, HDAC5 is a key determinant of the angiogenic gene expression profile: nuclear HDAC5 represses pro‑angiogenic genes, whereas VEGF and shear‑stress–induced export of HDAC5 enhances MEF2‑driven transcription, increases expression of angiogenic mediators, and promotes sprouting and tube formation. In cancer, HDAC5 is frequently dysregulated, and altered HDAC5 levels or localization affect proliferation, migration, epithelial–mesenchymal transition, cancer stemness, and drug sensitivity through deacetylation of chromatin and non‑histone substrates including RARA and SATB1. |
