Inhibition of histone methyltransferase EZH2 in Schistosoma mansoni by GSK343 decreases the expression of genes implicated in DNA replication and ncRNA metabolism

ABSTRACT: Schistosomiasis is a chronic and debilitating disease caused by a trematode of the genus Schistosoma. The current strategy for the control of the disease involves treatment with Praziquantel, the only available drug. The development of new drugs is therefore a top priority. Drugs that inhibit histone modifying enzymes have been used in cancer, altering gene expression, replication, repair and DNA recombination. Schistosoma parasites have some characteristics similar to malignant tumors, such as intense cell division and high levels of metabolic activity. Here we evaluate in Schistosoma mansoni the effect of GSK343, an inhibitor of the histone methyltransferase EZH2 that had been shown to arrest or reduce the growth of human cancer cells. We show that GSK343 causes damage to the parasite tegument and reduces egg laying in vitro, concomitant with a decrease in levels of H3K27me3, the histone mark put in place by EZH2. RNA-seq and proteomic analyses of treated parasites showed changes in the expression of hundreds of genes involved in important metabolic processes. In females, a marked decrease was observed in the expression of genes related to processes such as DNA replication and noncoding RNA metabolism. In conclusion, the histone methyltransferase EZH2 seems to be a promising novel drug target against schistosomiasis.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Schistosoma Mansoni (blood Fluke)

TISSUE(S): Whole Body

DISEASE(S): Schistosomiasis

SUBMITTER: David Pires  

LAB HEAD: Sergio Verjovski-Almeida

PROVIDER: PXD010342 | Pride | 2018-11-23

REPOSITORIES: Pride