title: Tumor cell survival dependence on the DHX9 DExH-box helicase.
abstract: The NTP-dependent DExH/D-box helicase DHX9 is a key participant in a number of gene regulatory steps, including transcriptional, translational, and microRNA-mediated control, DNA replication and maintenance of genomic stability. DHX9 has also been implicated in tumor cell maintenance and drug response. Here we report that inhibition of DHX9 expression is lethal to human cancer cell lines and murine Eμ-Myc lymphomas. Using a novel conditional shDHX9 mouse model, we demonstrate that sustained and prolonged (6 months) suppression of DHX9 does not result in any deleterious effects at the organismal level. Body weight, blood biochemistry and histology of various tissues were comparable to control mice. Global gene expression profiling revealed that, although reduction of DHX9 expression resulted in multiple transcriptome changes, these were relatively benign and did not lead to any discernible phenotype. Our results demonstrate a robust tolerance for systemic DHX9 suppression in vivo and support the targeting of DHX9 as an effective and specific chemotherapeutic approach.
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: T
authors.initials: T
authors.lastname: Lee
authors.affiliation: Département de Pathologie et Microbiologie, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, Québec.
authors.forename: M
authors.initials: M
authors.lastname: Paquet
authors.affiliation: Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
authors.forename: O
authors.identifier: 0000-0003-1412-1308
authors.initials: O
authors.lastname: Larsson
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec, Canada.|Department of Oncology, McGill University, Montreal, Quebec, Canada.|Rosalind and Morris Goodman Cancer Research Center, McGill University, Montreal, Quebec, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Pelletier
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors / Q000235:genetics*; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000235:genetics; D042822:Genomic Instability; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000235:genetics; D059467:Transcriptome / Q000235:genetics*
chemical_list: C506727:Dhx9 protein, mouse; D035683:MicroRNAs; D009363:Neoplasm Proteins; D053487:DEAD-box RNA Helicases