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

Deroanne, Christophe; Bonjean, Karine; Servotte, S.; Devy, Laetitia; Colige, Alain; Clausse, Nathalie; Blacher, Sylvia; Verdin, Eric; Foidart, Jean‐Michel; Nusgens, Betty; Castronovo, Vincent

doi:10.1038/sj.onc.1205108

Cited by 362 publications

(281 citation statements)

References 22 publications

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“…Here, we show a new mechanism by which DNMT and HDAC inhibitors might be used in anticancer therapy, for reversal of endothelial cell anergy. Together with our recent findings (19) and findings of others (20,53), showing that these compounds are powerful inhibitors of endothelial cell growth and tumor angiogenesis in vitro and in vivo, our current data show that DNMT and HDAC inhibitors have direct effects on tumor endothelial cells. Therefore, the therapeutic targets of these compounds can be extended beyond merely tumor cells.…”

Section: Discussionsupporting

confidence: 88%

Epigenetic Regulation of Tumor Endothelial Cell Anergy: Silencing of Intercellular Adhesion Molecule-1 by Histone Modifications

Hellebrekers

Castermans

Viré³

et al. 2006

Cancer Research

143

107

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Tumors can escape from immunity by repressing leukocyte adhesion molecule expression on tumor endothelial cells and by rendering endothelial cells unresponsive to inflammatory activation. This endothelial cell anergy is induced by angiogenic growth factors and results in reduced leukocytevessel wall interactions, thereby attenuating infiltration of leukocytes into the tumor. This report describes a novel mechanism of endothelial cell anergy regulation. We recently reported that DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors have angiostatic activity. Here, we studied whether epigenetic mechanisms regulate this angiogenesis-mediated escape from immunity. We found that DNMT inhibitors 5-aza-2 ¶-deoxycytidine and zebularine, as well as HDAC inhibitor trichostatin A, reexpressed intercellular adhesion molecule-1 (ICAM-1) on tumor-conditioned endothelial cells in vitro , resulting in restored leukocyte-endothelial cell adhesion. In addition, treatment with DNMT or HDAC inhibitors in vivo also restored ICAM-1 expression on tumor endothelial cells from two different mouse tumor models. Furthermore, leukocyte-vessel wall interactions in mouse tumors were increased by these compounds, as measured by intravital microscopy, resulting in enhanced leukocyte infiltration. We show that ICAM-1 down-regulation in tumor endothelial cells is associated with ICAM-1 promoter histone H3 deacetylation and loss of histone H3 Lys 4 methylation but not with DNA hypermethylation. In conclusion, our data show that ICAM-1 is epigenetically silenced in tumor endothelial cells by promoter histone modifications, which can be overcome by DNMT and HDAC inhibitors, suggesting a new molecular mechanism based on which novel therapeutic approaches for cancer can be

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Section: Discussionsupporting

confidence: 88%

Epigenetic Regulation of Tumor Endothelial Cell Anergy: Silencing of Intercellular Adhesion Molecule-1 by Histone Modifications

Hellebrekers

Castermans

Viré³

et al. 2006

Cancer Research

143

107

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“…TSA, vorinostat, FK228, butyrate and LAQ824 were found to repress angiogenesis in vitro and in vivo, and reduce expression of pro-angiogenesis factors, including HIF-1a and VEGF (Deroanne et al, 2002;Bolden et al, 2006;Liang et al, 2006). HDACi can induce HIF-1a degradation by acetylation at Lys532, leading to the interaction with, and ubiquitination by pVHL (Jeong et al, 2002).…”

Section: Hdaci Inhibits Angiogenesismentioning

confidence: 99%

“…HDACi inhibit angiogenesis by preventing endothelial cells from responding to the angiogenic stimulus generated by VEGF (Deroanne et al, 2002). TSA and vorinostat inhibit VEGF-induced expression of VEGF receptors and neuropilin-1, and induction of semaphoring III expression in endothelial cells.…”

Section: Hdaci Inhibits Angiogenesismentioning

confidence: 99%

Histone deacetylase inhibitors: molecular mechanisms of action

2007

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“…Undifferentiated embryonic stem CGR8 (ES) cells were aggregated by culture on bacteriological dishes during 4 days in a 20-#l hanging drop of DMEM supplemented with 10% FBS, 0.1 mM non-essential amino acids, 0.1 mM !-mercaptoethanol, and 10 ng/ml of VEGF to induce cell clustering and differentiation into endothelial cells [30]. The aggregates were seeded on gelatin-coated glass coverslips in the same medium supplemented with recombinant ADAMTS-2 or control sample.…”

Section: Embryoid Bodiesmentioning

confidence: 99%

ADAMTS-2 functions as anti-angiogenic and anti-tumoral molecule independently of its catalytic activity

Dubail¹,

Kesteloot²,

Deroanne³

et al. 2010

Cell. Mol. Life Sci.

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ADAMTS-2 is a metalloproteinase that plays a key role in the processing of fibrillar procollagen precursors into mature collagen molecules by excising the amino-propeptide. We demonstrate that recombinant ADAMTS-2 is also able to reduce proliferation of endothelial cells, and to induce their retraction and detachment from the substrate resulting in apoptosis. Dephosphorylation of Erk1/2 and MLC largely precedes the ADAMTS-2 induced morphological alterations. In 3-D culture models, ADAMTS-2 strongly reduced branching of capillarylike structures formed by endothelial cells and their long-term maintenance and inhibited vessels formation in embryoid bodies (EB). Growth and vascularization of tumors formed in nude mice by HEK 293-EBNA cells expressing ADAMTS-2 were drastically reduced. A similar anti-tumoral activity was observed when using cells expressing recombinant deleted forms of ADAMTS-2, including catalytically inactive enzyme. Nucleolin, a nuclear protein also found to be associated with the cell membrane, was identified as a potential receptor mediating the antiangiogenic properties of ADAMTS-2.

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

Cited by 362 publications

References 22 publications

Epigenetic Regulation of Tumor Endothelial Cell Anergy: Silencing of Intercellular Adhesion Molecule-1 by Histone Modifications

Epigenetic Regulation of Tumor Endothelial Cell Anergy: Silencing of Intercellular Adhesion Molecule-1 by Histone Modifications

Histone deacetylase inhibitors: molecular mechanisms of action

ADAMTS-2 functions as anti-angiogenic and anti-tumoral molecule independently of its catalytic activity

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