Role of the splicing factor SRSF4 in cisplatin-induced modifications of pre-mRNA splicing and apoptosis

Maude Gabriel, Yves Delforge, Adeline Deward, Yvette Habraken, Benoit Hennuy, Jacques Piette, Roscoe Klinck, Benoit Chabot, Alain Colige, Charles Lambert

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. 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. 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. Many of the splicing alterations induced by cisplatin are caused by SRSF4 and they contribute to apoptosis in a process requires class I PI3K.