Reference : Novel HDAC/DNMT Twin inhibitors interfere with angiogenesis
Scientific congresses and symposiums : Poster
Life sciences : Biochemistry, biophysics & molecular biology
Novel HDAC/DNMT Twin inhibitors interfere with angiogenesis
Shiva Shankar, Thammadihalli Veerasangaiah mailto [Université de Liège - ULiège > > > Form. doct. sc. agro. & ingé. biol.]
Sulka, Béatrice mailto [Université de Liège - ULiège > > GIGA-R : Epigénétique Cellulaire et Moléculaire >]
Blacher, Silvia mailto [Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement >]
Maillard, Catherine [Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement >]
Noël, Agnes mailto [> >]
Pendeville-Samain, Hélène [Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Biologie et génétique moléculaire >]
Lambert, Didier mailto [> >]
Wouters, Johan mailto [> >]
Willems, Luc mailto [Université de Liège - ULiège > Chimie et bio-industries > Centre de Bio. Fond. - Section de Biologie cell. et moléc. >]
GIGA day
[en] DNA methylation and histone deacetylation are two key epigenetic modifications that play central role in regulation of gene expression. Several studies have shown that histone deacetylases (HDAC) and DNA methyltransferases (DNMT) inhibitors are potent anti-angiogenic compounds. Though combination of HDAC and DNMT inhibitors are now being examined in clinical trials of hematological malignancies, little work has been done to understand the effect of this combination on physiological and tumoral angiogenesis. We have designed and tested a family of twin drugs with intrinsic HDAC and DNMT inhibitory activities in relevant models of angiogenesis in vitro (Human Umbilical Vein Endothelial Cells – HUVEC and aortic ring) and in vivo (chick chorioallantoic membrane and Zebrafish). We have identified a lead compound having quantifiable anti-angiogenic effect without cytotoxicity affecting global histone acetylation and DNA methylation levels. In order to elucidate its anti-angiogenic mechanism, we characterized gene expression pattern simultaneously with the methylation profile of HUVEC cells treated with the lead compound and reference epigenetic modulators. This approach based on parallel microarray analyses permitted us to underscore a list of genes exclusively affected by the lead compound but not by other HDAC or DNMT inhibitors. These genes were then analyzed using the Ingenuity Pathway software revealing potential involvement of a subset of genes in angiogenesis. Our present aim is to validate the expression levels of a series of genes with respect to epigenetic mechanisms (histone modifications and DNA methylation). Finally, the biological relevance of the target genes will be explored by RNA silencing. Hence, we are using these novel epigenetic modulators as a tool to understand the regulatory mechanism of angiogenesis and to develop effective approaches to treat cancer.

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