Effect of GSK343, an inhibitor of the histone methyltransferase EZH2, on the parasite Schistosoma mansoni

Abstract

Schistosomiasis is a parasitic infectious disease caused by trematode flatworms of the genus Schistosoma that affects over 250 million people worldwide. In Brazil, this parasitosis is one of the most serious public health problems, persisting due to the precarious conditions of life to which some populations are exposed. Control of the disease predominantly involves the administration of a single drug, praziquantel. Although it has chemotherapeutic efficacy and safety, there are reports that demonstrate resistance to the drug in endemic areas, thus showing the need to develop new schistosomicide compounds.Schistosoma mansoni is the only species responsible for schistosomiasis in Brazil. This parasite has a complex life cycle with several morpho-physiological peculiarities responsible for quick adaptation to different environments and hosts in which it is found. Recent studies have shown that, as in vertebrates, S. mansoni has a vast network of epigenetic marksthat could act in a stage-specific way on transcriptional control, what would result in different profiles of gene expression throughout its life cycle. The histone modifying enzymes (HME) is the central axes of the epigenetic regulation in eukaryotes, therefore are involved in different signaling pathways, including those that regulate cellular proliferation. Thus, the enzymes that regulate histone methylation (methyltransferases and histone demethylases) became targets for the development of new drugs against cancer. The histone methyltransferases (such as EZH2) are of great importance on chromatin remodeling processes, participating in the gene expression control by inserting repression marks on histone's residues. GSK343, a competitive inhibitor of EZH2 methyltransferase, was characterized by the Glaxo Smith Kline® company as an anti-cancer drug, and it was shown to be highly selective for human EZH2. The mechanisms of EZH2-regulated signaling pathways have neither been elucidated in S. mansoni, nor a detailed study of this enzyme as a potential new therapeutic target has been made yet. This drug has been recently tested in our research group, and we have seen that it has significant effects on the mortality of schistosomules and that it causes damage to the adult worms tegument (unpublished data). The present proposal aims to study the EZH2 inhibition response in S. mansoni using GSK343 as the treatment compound. We will assess the changes in the abundance of the histone H3K27me3 mark. Analysis of gene expression profile of the treated worms will also be performed by a high-throughput sequencing strategy (RNA-seq). In addition, proteomic assays will be performed in order to compare both transcriptional and translational profiles, and the consequent changes in the parasite phenotype (mortality, membrane changes, and motility). We expect that the data generated herein will elucidate key aspects on S. mansoni epigenetics that may be relevant to a variety of biological mechanisms crucial for the parasite survival. The characterization of a new potential molecular target and the establishment of an alternative therapeutic compound for the control of schistosomiasis will also be pursued. (AU)