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

Abstract

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: e 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: e production of VEGF was increased in HDAC1-and LL-37-transfected HaCaT 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. e 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. e expression of VEGF was high in cells co-transfected with pHDAC1-and pLL-37, and the expression decreased when pVHL was present.Conclusions: ese data demonstrate that HDAC1, LL-37 and VHL can modulate the production of VEGF via HIF-1alpha in HaCaT cells.

Trichostatin A resistance is facilitated by HIF-1α acetylation in HeLa human cervical cancer cells under normoxic conditions

“…Whereas no changes were shown in HIF-1α stability by HDAC1 or HDAC3 shRNA [ 17 ], HDAC1 and HDAC3 positively regulate HIF-1α stability via directly binding to the ODD domain of HIF-1α [ 21 ]. HDAC1 also regulates VEGF expression in normal keratinocytes (HaCaT cells) [ 31 ]. Endogenous HIF-1α increase by TSA treatment could hamper antitumor effect of TSA, which might be resulted in the reduction of TSA-mediated cell death.…”

Histone Deacetylases (HDACs) and Atherosclerosis: A Mechanistic and Pharmacological Review

“…Notably, VEGF could be induced by HIF-1α activation in response to hypoxia (Ikeda, 2005). Inhibition of HDAC1/4/6/7 abolished the expression of VEGF via impairing the induction or activity of HIF-1α in hypoxia-exposed ECV304 cells, HaCaT cells, or patients with chronic obstructive pulmonary disease (Granger et al, 2008;Reynoso-Roldán et al, 2012;To et al, 2012;Kowshik et al, 2014).…”

Cross Talk between Proliferative, Angiogenic, and Cellular Mechanisms Orchestred by HIF‐1α in Psoriasis

“…On the other hand, in hypoxia conditions, the degradation of HIF-1 α is interrupted because the PHDs are inactivated by the mitochondrial reactive oxygen species (ROS) leading to the accumulation HIF-1 α in the cytosol [ 49 , 50 ]. Under hypoxia, HDAC-1 and HDAC-7 are induced; meanwhile HDAC-1 downregulates the expression of VHL favouring the stabilization of HIF-1 α ( Figure 1 , h) [ 51 , 52 ] and HDAC-7 binds to HIF-1 α to cotranslocate to the nucleus [ 53 ].…”

“…Studying the regulation mechanisms for the VEGF production in keratinocytes, we found that HaCaT cells transfected with hdac-1 highly expressed VEGF via HIF-1 α ( Figure 1 , h), and HaCaT cells transfected with vhl scarcely produced VEGF ( Figure 1 , g), but the low production of VEGF could be counteracted by hdac-1 cotransfection. ( Figure 1 , g and h) [ 52 ]. These assays showed the direct and opposed effect of HDAC-1 and VHL over VEGF production via HIF-1 α ( Figure 1 , g and h).…”

“…Our group has demonstrated that in keratinocytes transfected with hdac-1 HIF-1 α translocated to the nuclei and the production of VEGF was induced, but the treatment with trichostatin-A inhibited that process. It is known that HDAC-1 induces the downexpression of VHL which leads HIF-1 α to proteasomal degradation [ 51 , 52 ]. Perhaps in the psoriasis Treg cells treated with trichostatin-A occurred that when HDAC-1 was inhibited, the expression of VHL augmented, HIF-1 α was proteolyzed ( Figure 1 , h), and the expression of IL-17 decreased, giving as result that Treg cells could not switch to Th17.…”