title: Histone deacetylase inhibitors interfere with angiogenesis by decreasing endothelial VEGFR-2 protein half-life in part via a VE-cadherin-dependent mechanism.
abstract: Recent evidence suggests that histone deacetylase inhibitors (HDACi) may mediate part of their antitumor effects by interfering with tumor angiogenesis. As signalling via the vascular endothelial growth factor receptor-2 (VEGFR-2) pathway is critical for angiogenic responses during tumor progression, we explored whether established antitumor effects of HDACi are partly mediated through diminished endothelial VEGFR-2 expression. We therefore examined the potential impact of three different HDACi, trichostatin A (TSA), sodium butyrate (But) and valproic acid (VPA), on VEGFR-2 protein expression. TSA, VPA and But significantly inhibit VEGFR-2 protein expression in endothelial cells. Pertinent to these data, VEGFR-2 protein half-life is shown to be decreased in response to HDACi. Recently, it could be demonstrated that expression of VE-cadherin influences VEGFR-2 protein half-life. In our experiments, VEGFR-2 downregulation was accompanied by HDACi-induced VE-cadherin suppression. Interestingly, siRNA-mediated knockdown of VE-cadherin led to a pronounced loss of VEGFR-2 expression on the protein as well as on the mRNA level, implicating that VE-cadherin not only influences VEGFR-2 protein half-life but also the transcriptional level. To further distinguish which of the eight different histone deacetylases are responsible for the regulation of VEGFR-2 expression, specific HDAC genes were silenced by transfecting respective siRNAs. These studies revealed that HDACs 1, 4, 5 and 6 are preferentially involved in VEGFR-2 expression. Therefore, these results provide an explanation for the anti-angiogenic action of HDAC inhibitors via a VE-cadherin, HDAC 1 and HDACs 4-6-mediated suppression of VEGFR-2 expression and might be of importance in the development of new anti-angiogenic drugs.
authors.affiliation: Department of Dermatology, Venereology and Allergology, Johann Wolfgang Goethe-University, Frankfurt/Main, Germany.
authors.forename: Igor
authors.initials: I
authors.lastname: Hrgovic
authors.affiliation: Department of Dermatology, Venereology and Allergology, Johann Wolfgang Goethe-University, Frankfurt/Main, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Doll
authors.affiliation: Department of Dermatology, Venereology and Allergology, Johann Wolfgang Goethe-University, Frankfurt/Main, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Pinter
authors.affiliation: Department of Dermatology, Venereology and Allergology, Johann Wolfgang Goethe-University, Frankfurt/Main, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Kaufmann
authors.affiliation: Department of Dermatology, Venereology and Allergology, Johann Wolfgang Goethe-University, Frankfurt/Main, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kippenberger
authors.affiliation: Department of Dermatology, Venereology and Allergology, Johann Wolfgang Goethe-University, Frankfurt/Main, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Meissner
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D020148:Butyric Acid / Q000494:pharmacology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D004727:Endothelium / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006207:Half-Life; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism; D000073864:Histone Deacetylase 6 / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism*; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D020148:Butyric Acid; D015820:Cadherins; D056284:Histone Deacetylase 1; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D014635:Valproic Acid; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099152:Cadherin 5; C012589:trichostatin A; C000588866:KDR protein, human; C400300:HDAC4 protein, human; C404500:HDAC5 protein, human; C433811:HDAC6 protein, human
keywords: HDACs 1, 4, 5 and 6; VE-cadherin; VEGFR-2; angiogenesis; histone deacetylase inhibitors; protein half-life