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.

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“…Cellular growth factors also play an important role in inducing angiogenesis by acting on their receptors to start downstream signal transduction and promote the proliferation and migration of VECs [ 4 ]. For example, vascular endothelial growth factor (VEGF) and its receptor, VEGFR, can activate the PI3K/AKT pathway to trigger revascularization [ 12 ]. Angiopoietin-1 (ang-1), which is also related to endothelial cell survival, proliferation, and migration, can reduce endothelial permeability and promote the maturation and stability of newly formed blood vessels by interacting with the tyrosine kinase TIE-2 receptor [ 6 , 14 ].…”

Single-cell RNA-seq identifies a reversible epithelial-mesenchymal transition in abnormally specified epithelia of p63 EEC syndrome

“…Suramin, are known to repress the mesodermal lineage or interfere with EMT (34,35,(36)(37)(38). Heparin and VA seemed to be more effective in improving epidermal KC maturation, whereas Suramin was more efficient in rescuing differentiation defects of EEC-PSCs.…”

“…As it has been reported that p63 can repress epithelial-mesenchymal transition (EMT) in cancers (29,30), we hypothesized that normal p63 may have similar function in inhibiting the embryonic EMT during development, and EEC mutations affect the EMT repression controlled by p63. To assess whether the mesodermal activation is causal to the commitment defects of these EEC iPSC, three compounds that were shown to repress the mesodermal lineage differentiation, Heparin, valproic acid (VA) and Suramin (31)(32)(33)(34)(35) were tested. As our day-30 iKCs seemed to retain some multipotent signatures, repressing mesodermal differentiation may also facilitate epidermal maturation.…”

Angiogenesis and Cardiovascular Diseases: The Emerging Role of HDACs

“…Other HDACi also exert similar efects, as exempliied by MPT0G157, a potent inhibitor of HDAC1, 2, 3, and 6, which was found to promote HIF-1α degradation followed by the downregulation of VEGF expression [92]. There are also reports of the anti-tumoural efects of other HDACi (TSA, sodium butyrate, and VPA) that are also partly mediated by the reduction of VEGFR-2 expression that might be related to repressing tumour angiogenesis [93].…”