SRSF3-regulated RNA alternative splicing promotes glioblastoma tumorigenicity by affecting multiple cellular processes

Xiao Song, Xuechao Wan, Tianzhi Huang, Chang Zeng, Namratha Sastry, Bingli Wu, C. David James, Craig Horbinski, Ichiro Nakano, Wei Zhang, Bo Hu, Shi Yuan Cheng*

*Corresponding author for this work

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Misregulated alternative RNA splicing (AS) contributes to the tumorigenesis and progression of human cancers, including glioblastoma (GBM). Here, we showed that a major splicing factor, serine and arginine rich splicing factor 3 (SRSF3), was frequently upregulated in clinical glioma specimens and that elevated SRSF3 was associated with tumor progression and a poor prognosis for patients with glioma. In patient-derived glioma stem-like cells (GSC), SRSF3 expression promoted cell proliferation, self-renewal, and tumorigenesis. Transcriptomic profiling identified more than 1,000 SRSF3-affected AS events, with a preference for exon skipping in genes involved with cell mitosis. Motif analysis identified the sequence of CA(G/C/A)CC(C/A) as a potential exonic splicing enhancer for these SRSF3-regulated exons. To evaluate the biological impact of SRSF3-affected AS events, four candidates were selected whose AS correlated with SRSF3 expression in glioma tissues, and their splicing pattern was modified using a CRISPR/Cas9 approach. Two functionally validated AS candidates were further investigated for the mechanisms underlying their isoform-specific functions. Specifically, following knockout of SRSF3, transcription factor ETS variant 1 (ETV1) gene showed exon skipping at exon 7, while nudE neurodevelopment protein 1 (NDE1) gene showed replacement of terminal exon 9 with a mutually exclusive exon 90. SRSF3-regulated AS of these two genes markedly increased their oncogenic activity in GSCs. Taken together, our data demonstrate that SRSF3 is a key regulator of AS in GBM and that understanding mechanisms of misregulated AS could provide critical insights for developing effective therapeutic strategies against GBMs.

Original languageEnglish (US)
Pages (from-to)5288-5301
Number of pages14
JournalCancer Research
Volume79
Issue number20
DOIs
StatePublished - Oct 15 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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