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

Publisher: BioMed Central Country of Publication: England NLM ID: 100967800 Publication Model: Electronic Cited Medium: Internet ISSN: 1471-2407 (Electronic) Linking ISSN: 14712407 NLM ISO Abbreviation: BMC Cancer Subsets: MEDLINE

Original Publication: London : BioMed Central, [2001-

Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Cisplatin/*pharmacology ; RNA Precursors/*genetics ; RNA Splicing/*drug effects ; RNA-Binding Proteins/*metabolism; Cell Line, Tumor ; Computational Biology ; DNA Damage ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Oncogene Proteins/genetics ; Oncogene Proteins/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; RNA Processing, Post-Transcriptional/drug effects ; Serine-Arginine Splicing Factors ; Signal Transduction/drug effects ; Transcription Factors/metabolism ; Tumor Suppressor Protein p53/metabolism ; Tumor Suppressor Proteins/genetics ; Tumor Suppressor Proteins/metabolism

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

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MOP136948 Canada Canadian Institutes of Health Research

0 (Antineoplastic Agents)
0 (Oncogene Proteins)
0 (RNA Precursors)
0 (RNA-Binding Proteins)
0 (SRSF4 protein, human)
0 (Transcription Factors)
0 (Tumor Suppressor Protein p53)
0 (Tumor Suppressor Proteins)
170974-22-8 (Serine-Arginine Splicing Factors)
EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
Q20Q21Q62J (Cisplatin)

Date Created: 20150418 Date Completed: 20160106 Latest Revision: 20181113

20240104

PMC4399393

10.1186/s12885-015-1259-0

25884497