gms | German Medical Science

Recent evidence suggests that histone deacetylase (HDAC) inhibitors may mediate part of their antitumor effects by interfering with tumor angiogenesis. As signaling via the vascular endothelial growth factor receptor-2 (VEGFR2) pathway is critical for angiogenic responses during tumor progression, we explored whether established antitumor effects of HDAC inhibitors are mediated in part through diminished VEGFR2 expression. We therefore examined the potential impact of three different HDAC inhibitors, trichostatin A (TSA), sodium butyrate (NaB) and valproic acid (VPA), on mRNA and protein VEGFR2 expression. In contrast to VAP, TSA and NaB are shown to significantly inhibit VEGFR2 protein expression in a time- and concentration-dependent manner, whereas no such effect is demonstrated at the level of mRNA expression. Pertinent to these data, VEGFR2 protein half-life is shown to be decreased in response to TSA and NaB. First experimental evidence indicates that reduction of protein half-life may be mediated in part via HDAC inhibitor-induced expression of the ubiquitin ligase CBL. To further distinguish as to which of the eight different histone deacetylases are responsible for the regulation of VEGFR2 protein half-life, specific HDAC genes were silenced by transfecting respective siRNAs. These studies revealed that HDACs 4 and 6 are preferentially involved in VEGFR2 expression, providing first evidence for the regulation of a tyrosine kinase receptor protein half-life by distinct HDACs. Together, VEGFR2 protein expression may represent an important target of HDAC inhibitors in mediating antitumor effects, an assumption that is supported by data also showing significant inhibition of capillary network formation in vitro.