title: Role of the splicing factor SRSF4 in cisplatin-induced modifications of pre-mRNA splicing and apoptosis.
abstract: BACKGROUND
  Modification of splicing by chemotherapeutic drugs has usually been evaluated on a limited number of pre-mRNAs selected for their recognized or potential importance in cell proliferation or apoptosis. However, the pathways linking splicing alterations to the efficiency of cancer therapy remain unclear.
  
  
  METHODS
  Next-generation sequencing was used to analyse the transcriptome of breast carcinoma cells treated by cisplatin. Pharmacological inhibitors, RNA interference, cells deficient in specific signalling pathways, RT-PCR and FACS analysis were used to investigate how the anti-cancer drug cisplatin affected alternative splicing and the cell death pathway.
  
  
  RESULTS
  We identified 717 splicing events affected by cisplatin, including 245 events involving cassette exons. Gene ontology analysis indicates that cell cycle, mRNA processing and pre-mRNA splicing were the main pathways affected. Importantly, the cisplatin-induced splicing alterations required class I PI3Ks P110β but not components such as ATM, ATR and p53 that are involved in the DNA damage response. The siRNA-mediated depletion of the splicing regulator SRSF4, but not SRSF6, expression abrogated many of the splicing alterations as well as cell death induced by cisplatin.
  
  
  CONCLUSIONS
  Many of the splicing alterations induced by cisplatin are caused by SRSF4 and they contribute to apoptosis in a process requires class I PI3K.
authors.affiliation: Laboratory of Connective Tissues Biology, GIGA-Cancer, University of Liège, avenue de l'Hôpital 1, 4000, Liège, Belgium. maude.gabriel@ulg.ac.be.
authors.forename: Maude
authors.initials: M
authors.lastname: Gabriel
authors.affiliation: Laboratory of Connective Tissues Biology, GIGA-Cancer, University of Liège, avenue de l'Hôpital 1, 4000, Liège, Belgium. yves.delforge@ulg.ac.be.
authors.forename: Yves
authors.initials: Y
authors.lastname: Delforge
authors.affiliation: Laboratory of Virology and Immunology, GIGA-Signal Transduction, GIGA B34, University of Liège, avenue de l'Hôpital 1, 4000, Liège, Belgium. adeward@ulg.ac.be.
authors.forename: Adeline
authors.initials: A
authors.lastname: Deward
authors.affiliation: Laboratory of Virology and Immunology, GIGA-Signal Transduction, GIGA B34, University of Liège, avenue de l'Hôpital 1, 4000, Liège, Belgium. Yvette.habraken@ulg.ac.be.
authors.forename: Yvette
authors.initials: Y
authors.lastname: Habraken
authors.affiliation: GIGA Genomics Platform, University of Liège, avenue de l'Hôpital 1, 4000, Liège, Belgium. benoit.hennuy@ulg.ac.be.
authors.forename: Benoit
authors.initials: B
authors.lastname: Hennuy
authors.affiliation: Laboratory of Virology and Immunology, GIGA-Signal Transduction, GIGA B34, University of Liège, avenue de l'Hôpital 1, 4000, Liège, Belgium. jpiette@ulg.ac.be.
authors.forename: Jacques
authors.initials: J
authors.lastname: Piette
authors.affiliation: Laboratory of Functional Genomics and Department of Microbiology and Infectiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada. roscoe.klinck@usherbrooke.ca.
authors.forename: Roscoe
authors.initials: R
authors.lastname: Klinck
authors.affiliation: Laboratory of Functional Genomics and Department of Microbiology and Infectiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada. benoit.chabot@usherbrooke.ca.
authors.forename: Benoit
authors.initials: B
authors.lastname: Chabot
authors.affiliation: Laboratory of Connective Tissues Biology, GIGA-Cancer, University of Liège, avenue de l'Hôpital 1, 4000, Liège, Belgium. acolige@ulg.ac.be.
authors.forename: Alain
authors.initials: A
authors.lastname: Colige
authors.affiliation: Laboratory of Connective Tissues Biology, GIGA-Cancer, University of Liège, avenue de l'Hôpital 1, 4000, Liège, Belgium. c.lambert@ulg.ac.be.
authors.forename: Charles
authors.initials: C
authors.lastname: Lambert
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019295:Computational Biology; D004249:DNA Damage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D012322:RNA Precursors / Q000235:genetics*; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects; D012326:RNA Splicing / Q000187:drug effects*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D000068103:Serine-Arginine Splicing Factors; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D015513:Oncogene Proteins; D012322:RNA Precursors; D016601:RNA-Binding Proteins; C081934:SRSF4 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000068103:Serine-Arginine Splicing Factors; D019869:Phosphatidylinositol 3-Kinases; D002945:Cisplatin