title: Epigenetic regulation of tumor endothelial cell anergy: silencing of intercellular adhesion molecule-1 by histone modifications.
abstract: 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 leukocyte-vessel 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 pursued.
authors.affiliation: Angiogenesis Laboratory, Research Institute for Growth and Development, Department of Pathology, Maastricht University and University Hospital, The Netherlands.
authors.forename: Debby M E I
authors.initials: DM
authors.lastname: Hellebrekers
authors.forename: Karolien
authors.initials: K
authors.lastname: Castermans
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Viré
authors.forename: Ruud P M
authors.initials: RP
authors.lastname: Dings
authors.forename: Nicole T H
authors.initials: NT
authors.lastname: Hoebers
authors.forename: Kevin H
authors.initials: KH
authors.lastname: Mayo
authors.forename: Mirjam G A
authors.initials: MG
authors.lastname: Oude Egbrink
authors.forename: Grietje
authors.initials: G
authors.lastname: Molema
authors.forename: François
authors.initials: F
authors.lastname: Fuks
authors.forename: Manon
authors.initials: M
authors.lastname: van Engeland
authors.forename: Arjan W
authors.initials: AW
authors.lastname: Griffioen
mesh_terms: D000107:Acetylation; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D017635:Clonal Anergy; D003562:Cytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015536:Down-Regulation; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics*; D007962:Leukocytes / Q000473:pathology; D008546:Melanoma, Experimental / Q000097:blood / Q000473:pathology; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D018799:Intercellular Adhesion Molecule-1; D003562:Cytidine; C009131:pyrimidin-2-one beta-ribofuranoside; D015254:DNA Modification Methylases; D006655:Histone Deacetylases