title: Splicing switch of an epigenetic regulator by RNA helicases promotes tumor-cell invasiveness.
abstract: Both epigenetic and splicing regulation contribute to tumor progression, but the potential links between these two levels of gene-expression regulation in pathogenesis are not well understood. Here, we report that the mouse and human RNA helicases Ddx17 and Ddx5 contribute to tumor-cell invasiveness by regulating alternative splicing of several DNA- and chromatin-binding factors, including the macroH2A1 histone. We show that macroH2A1 splicing isoforms differentially regulate the transcription of a set of genes involved in redox metabolism. In particular, the SOD3 gene that encodes the extracellular superoxide dismutase and plays a part in cell migration is regulated in an opposite manner by macroH2A1 splicing isoforms. These findings reveal a new regulatory pathway in which splicing factors control the expression of histone variant isoforms that in turn drive a transcription program to switch tumor cells to an invasive phenotype.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Dardenne
authors.forename: Sandra
authors.initials: S
authors.lastname: Pierredon
authors.forename: Keltouma
authors.initials: K
authors.lastname: Driouch
authors.forename: Lise
authors.initials: L
authors.lastname: Gratadou
authors.forename: Magali
authors.initials: M
authors.lastname: Lacroix-Triki
authors.forename: Micaela Polay
authors.initials: MP
authors.lastname: Espinoza
authors.forename: Eleonora
authors.initials: E
authors.lastname: Zonta
authors.forename: Sophie
authors.initials: S
authors.lastname: Germann
authors.forename: Hussein
authors.initials: H
authors.lastname: Mortada
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Villemin
authors.forename: Martin
authors.initials: M
authors.lastname: Dutertre
authors.forename: Rosette
authors.initials: R
authors.lastname: Lidereau
authors.forename: Stéphan
authors.initials: S
authors.lastname: Vagner
authors.forename: Didier
authors.initials: D
authors.lastname: Auboeuf
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D044127:Epigenesis, Genetic / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006657:Histones / Q000235:genetics*; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000503:physiopathology; D012372:ROC Curve; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D017931:DNA Primers; D006657:Histones; C120756:macroH2A histone; C441642:SOD3 protein, human; D013482:Superoxide Dismutase; C102004:DDX17 protein, human; C506749:Ddx5 protein, human; D053487:DEAD-box RNA Helicases