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Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling

Abstract

Angiogenesis is a complex biological process involving the coordinated modulation of many genes. Histone deacetylases (HDAC) are a growing family of enzymes that mediate the availability of chromatin to the transcriptional machinery. Trichostatin-A (TSA) and suberoylanilide hydroxamic acid (SAHA), two HDAC inhibitors known to relieve gene silencing, were evaluated as potential antiangiogenic agents. TSA and SAHA were shown to prevent vascular endothelial growth factor (VEGF)-stimulated human umbilical cord endothelial cells (HUVEC) from invading a type I collagen gel and forming capillary-like structures. SAHA and TSA inhibited the VEGF-induced formation of a CD31-positive capillary-like network in embryoid bodies and inhibited the VEGF-induced angiogenesis in the CAM assay. TSA also prevented, in a dose-response relationship, the sprouting of capillaries from rat aortic rings. TSA inhibited in a dose-dependent and reversible fashion the VEGF-induced expression of VEGF receptors, VEGFR1, VEGFR2, and neuropilin-1. TSA and SAHA upregulated the expression by HUVEC of semaphorin III, a recently described VEGF competitor, at both mRNA and protein levels. This effect was specific to endothelial cells and was not observed in human fibroblasts neither in vascular smooth muscle cells. These observations provide a conspicuous demonstration that HDAC inhibitors are potent anti-angiogenic factors altering VEGF signaling.

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Acknowledgements

We are grateful to Christian Dani for the kind gift of ES CGR8 cells and to Clotilde Gimond, Sandrine Marchetti and Christine Bourcier (CNRS-UMR6543, J Pouysségur) for help with EB cultures, to M Tessier-Lavigne for the kind gift of semaphorin-III probe and to Marie-Jeanne Nix and Antoine Heyeres for excellent technical assistance. This work received financial support from the Belgian FNRS, the ‘Centre Anticancéreux près l'Université de Liège' and the FNRS-Télévie. C Deroanne is a Postdoctoral Researcher of the FNRS and A Colige is a Research Associate of the FNRS.

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Correspondence to Christophe F Deroanne.

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Deroanne, C., Bonjean, K., Servotte, S. et al. Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling. Oncogene 21, 427–436 (2002). https://doi.org/10.1038/sj.onc.1205108

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