| HDAC7 is a class IIa histone deacetylase that shuttles between the nucleus and cytoplasm and functions as a signaling‑responsive transcriptional corepressor, integrating phosphorylation cues with deacetylase‑complex assembly to control lineage decisions, survival, and stress adaptation in multiple tissues, including vascular endothelium, heart, skeletal muscle, and immune cells. The protein contains an N‑terminal regulatory region rich in serine residues targeted by kinases and docking sites for 14‑3‑3 proteins, and a C‑terminal catalytic module that associates with HDAC3, NCoR/SMRT, and other corepressors rather than displaying high intrinsic deacetylase activity, so its repressive output largely depends on recruitment of this larger complex to specific transcription factors and chromatin regions. Phosphorylation of conserved serines in the N‑terminus by kinases such as PKD, CaMK, or MARK promotes binding to 14‑3‑3 proteins and nuclear export, which relieves repression of HDAC7 target genes, whereas dephosphorylated HDAC7 accumulates in the nucleus, where it binds MEF2 and other transcription factors to recruit HDAC3‑corepressor complexes and enforce histone deacetylation and gene silencing, establishing a phospho‑switch that couples upstream Ca²⁺/PKD and stress pathways to transcriptional programs. During cardiovascular development and remodeling, HDAC7 is essential for vascular integrity and cardiac growth control: nuclear HDAC7 in endothelial and cardiac cells represses MEF2‑dependent and other pro‑angiogenic or hypertrophic genes, while stimulus‑driven phosphorylation and export of HDAC7 permit MEF2 activation, angiogenic gene expression, and, as shown in recent work, cardiomyocyte proliferation through derepression of cell‑cycle regulators required for myocardial expansion and regeneration. In skeletal muscle and myoblasts, HDAC7 similarly restrains differentiation by binding MEF2 and maintaining a deacetylated, transcriptionally repressed chromatin state at muscle‑specific loci, with nuclear export of HDAC7 during differentiation allowing MEF2‑driven expression of contractile and metabolic genes and thereby linking class IIa HDAC localization to myogenic progression. Across a wide range of solid tumors and hematologic malignancies, HDAC7 is frequently dysregulated at the mRNA and protein levels, and pan‑cancer analyses indicate that high HDAC7 expression correlates with enhanced proliferation, angiogenesis, epithelial–mesenchymal transition signatures, and resistance to chemotherapy, in part through repression of tumor suppressors and modulation of STAT3 and β‑catenin signaling and in part via regulation of super‑enhancer–linked oncogenes in specific contexts such as breast cancer stem‑like cells. |
