Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni
German Cancer Research Center ; Universidade Federal do Rio de Janeiro (UFRJ) ; Universidade de São Paulo (USP) ; University of Groningen ; Sapienza University of Rome ; Universidade do Estado do Rio de Janeiro (UERJ) ; Martin Luther University Halle-Wittenberg (MLU) ; Université de Lille ; Institut Pasteur de Lille ; Centre de Recherche en Cancérologie de Marseille (CRCM) ; Aix-Marseille Université ; University of East Anglia (UEA) ; Fundação Oswaldo Cruz (Fiocruz) ; Instituto Oswaldo Cruz (IOC) ; Instituto René Rachou (Fiocruz Minas)
Appears in Collections:
Treatment and control of schistosomiasis still rely on only one effective drug, praziquantel (PZQ) and, due to mass treatment, the increasing risk of selecting for schistosome strains that are resistant to PZQ has alerted investigators to the urgent need to develop novel therapeutic strategies. The histone-modifying enzymes (HMEs) represent promising targets for the development of epigenetic drugs against Schistosoma mansoni. In the present study, we targeted the S. mansoni lysine-specific demethylase 1 (SmLSD1), a transcriptional corepressor, using a novel and selective synthetic inhibitor, MC3935, which was used to treat schistosomula and adult worms in vitro. By using cell viability assays and optical and electron microscopy, we showed that treatment with MC3935 affected parasite motility, egg-laying, tegument, and cellular organelle structures, culminating in the death of schistosomula and adult worms. In silico molecular modeling and docking analysis suggested that MC3935 binds to the catalytic pocket of SmLSD1. Western blot analysis revealed that MC3935 inhibited SmLSD1 demethylation activity of H3K4me1/2. Knockdown of SmLSD1 by RNAi recapitulated MC3935 phenotypes in adult worms. RNA-Seq analysis of MC3935-treated parasites revealed significant differences in gene expression related to critical biological processes. Collectively, our findings show that SmLSD1 is a promising drug target for the treatment of schistosomiasis and strongly support the further development and in vivo testing of selective schistosome LSD1 inhibitors.
Carneiro VC, Silva ICA, Amaral MS, Pereira ASA, Silveira GO, Pires DS, et al. Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni. Plos Negl. Trop. Dis.. 2020 Jul;14(7):e0008332. doi:10.1371/journal.pntd.0008332.
Link to cite this reference
European Union’s Seventh Framework Programme ; Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) ; Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) ; Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) ; European Regional Development Fund (ERDF) ; Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)
The access to the publications deposited in this repository respects the licenses from journals and publishers.