Vascular endothelial growth factor production is induced by histone deacetylase 1 and suppressed by von Hippel-Lindau protein in HaCaT cells

Purpose: In hypoxic tumoral tissues, vascular endothelial growth factor (VEGF) expression is positively regulated by histone deacetylase 1 (HDAC1) and negatively regulated by the tumour suppressor protein von Hippel-Lindau (VHL) via hypoxia induced factor-1 alpha (HIF-1alpha). It has been reported that VEGF, HDAC1 and LL-37, but not VHL, are over-expressed in psoriatic skin. Although HIF-1alpha is constitutively expressed in normal keratinocytes, it is not known if HDAC1 and VHL can regulate VEGF production in these cells. Methods: The participation of HDAC1 and VHL in the regulation of VEGF expression in HDAC1-, VHL-and LL-37-transfected HaCaT cells, and in HaCaT cells treated with HDAC1 inhibitors, was studied. Results: The production of VEGF was increased in HDAC1-and LL-37-transfected Ha-CaT cells and maintained in VHL-transfected cells under hypoxic conditions; meanwhile, VEGF production decreased in HaCaT cells treated with TSA, in cells transfected with HDAC1-siRNA, in cells co-transfected with HIF-1alpha-siRNA and pHDAC-1 and in VHL-transfected HaCaT cells. The levels of cytoplasmic HIF-1alpha were high in pLL37-transfected cells and low in pVHL-and pHDAC1-transfected cells; however, HIF-1alpha was detected in the nucleus of the HDAC1-transfected cells. The expression of VEGF was high in cells co-transfected with pHDAC1-and pLL-37, and the expression decreased when pVHL was present. Conclusions: These data demonstrate that HDAC1, LL-37 and VHL can modulate the production of VEGF via HIF-1alpha in HaCaT cells.