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Histone deacetylase inhibitors interfere with angiogenesis by decreasing endothelial VEGFR ‐2 protein half‐life in part via a VE ‐cadherin‐dependent mechanism
Author(s) -
Hrgovic Igor,
Doll Monika,
Pinter Andreas,
Kaufmann Roland,
Kippenberger Stefan,
Meissner Markus
Publication year - 2017
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/exd.13159
Subject(s) - trichostatin a , histone deacetylase , gene knockdown , angiogenesis , small interfering rna , cancer research , histone deacetylase inhibitor , downregulation and upregulation , sodium butyrate , biology , hdac4 , vorinostat , chemistry , microbiology and biotechnology , histone , transfection , biochemistry , gene
Recent evidence suggests that histone deacetylase inhibitors ( HDAC i) 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 HDAC i, 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 HDAC i. 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 HDAC i‐induced VE ‐cadherin suppression. Interestingly, si RNA ‐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 si RNA s. These studies revealed that HDAC s 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 HDAC s 4–6‐mediated suppression of VEGFR ‐2 expression and might be of importance in the development of new anti‐angiogenic drugs.