Histone deacetylase 7 silencing alters endothelial cell migration, a key step in angiogenesis.
Global inhibition of class I and II histone deacetylases (HDACs) impairs angiogenesis. Herein, we have undertaken the identification of the specific HDAC(s) with activity that is necessary for the development of blood vessels. Using small interfering RNAs, we observed that HDAC7 silencing in endothelial cells altered their morphology, their migration, and their capacity to form capillary tube-like structures in vitro but did not affect cell adhesion, proliferation, or apoptosis. Among several factors known to be involved in angiogenesis, platelet-derived growth factor-B (PDGF-B) and its receptor (PDGFR-beta) were the most upregulated genes following HDAC7 silencing. We demonstrated that their increased expression induced by HDAC7 silencing was partially responsible for the inhibition of endothelial cell migration. In addition, we have also shown that treatment of endothelial cells with phorbol 12-myristate 13-acetate resulted in the exportation of HDAC7 out of the nucleus through a protein kinase C/protein kinase D activation pathway and induced, similarly to HDAC7 silencing, an increase in PDGF-B expression, as well as a partial inhibition of endothelial cell migration. Collectively, these data identified HDAC7 as a key modulator of endothelial cell migration and hence angiogenesis, at least in part, by regulating PDGF-B/PDGFR-beta gene expression. Because angiogenesis is required for tumor progression, HDAC7 may represent a rational target for therapeutic intervention against cancer.
Mottet
Denis
D
Metastasis Research Laboratory, University of Liège, Belgium.
Bellahcène
Akeila
A
Pirotte
Sophie
S
Waltregny
David
D
Deroanne
Christophe
C
Lamour
Virginie
V
Lidereau
Rosette
R
Castronovo
Vincent
V
D002465:Cell Movement / Q000235:genetics*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology* / Q000201:enzymology* / Q000378:metabolism; D020868:Gene Silencing / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D018919:Neovascularization, Physiologic / Q000235:genetics*; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D017479:Receptors, Platelet-Derived Growth Factor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics
D056572:Histone Deacetylase Inhibitors; D010982:Platelet-Derived Growth Factor; D017479:Receptors, Platelet-Derived Growth Factor; C543273:HDAC7 protein, human; D006655:Histone Deacetylases