A ruthenium anticancer compound interacts with histones and impacts differently on epigenetic and death pathways compared to cisplatin
Résumé
Ruthenium complexes are considered as potential replacements for platinum
compounds in oncotherapy. Their clinical development is handicapped by a lack
of consensus on their mode of action. In this study, we identify three histones
(H3.1, H2A, H2B) as possible targets for an anticancer redox organoruthenium
compound (RDC11). Using puriied histones, we conirmed an interaction between
the ruthenium complex and histones that impacted on histone complex formation.
A comparative study of the ruthenium complex versus cisplatin showed differential
epigenetic modiications on histone H3 that correlated with differential expression
of histone deacetylase (HDAC) genes. We then characterized the impact of these
epigenetic modiications on signaling pathways employing a transcriptomic
approach. Clustering analyses showed gene expression signatures speciic for
cisplatin (42%) and for the ruthenium complex (30%). Signaling pathway analyses
pointed to speciicities distinguishing the ruthenium complex from cisplatin. For
instance, cisplatin triggered preferentially p53 and folate biosynthesis while the
ruthenium complex induced endoplasmic reticulum stress and trans-sulfuration
pathways. To further understand the role of HDACs in these regulations, we used
suberanilohydroxamic acid (SAHA) and showed that it synergized with cisplatin
cytotoxicity while antagonizing the ruthenium complex activity. This study provides
critical information for the characterization of signaling pathways differentiating
both compounds, in particular, by the identiication of a non-DNA direct target for
an organoruthenium complex.