Splicing factor SRSF1 promotes gliomagenesis via oncogenic splice-switching of MYO1B
Xuexia Zhou, … , Qian Wang, Shizhu Yu
Xuexia Zhou, … , Qian Wang, Shizhu Yu
Published February 1, 2019; First published November 27, 2018
Citation Information: J Clin Invest. 2019;129(2):676-693. https://doi.org/10.1172/JCI120279.
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Research Article Cell biology Oncology

Splicing factor SRSF1 promotes gliomagenesis via oncogenic splice-switching of MYO1B

Abstract

Abnormal alternative splicing (AS) caused by alterations to splicing factors contributes to tumor progression. Serine/arginine splicing factor 1 (SRSF1) has emerged as a key oncodriver in numerous solid tumors, leaving its roles and mechanisms largely obscure in glioma. Here, we demonstrate that SRSF1 is increased in glioma tissues and cell lines. Moreover, its expression was correlated positively with tumor grade and Ki-67 index, but inversely with patient survival. Using RNA-Seq, we comprehensively screened and identified multiple SRSF1-affected AS events. Motif analysis revealed a position-dependent modulation of AS by SRSF1 in glioma. Functionally, we verified that SRSF1 promoted cell proliferation, survival, and invasion by specifically switching the AS of the myosin IB (MYO1B) gene and facilitating the expression of the oncogenic and membrane-localized isoform, MYO1B-fl. Strikingly, MYO1B splicing was dysregulated in parallel with SRSF1 expression in gliomas and predicted the poor prognosis of the patients. Further investigation revealed that SRSF1-guided AS of the MYO1B gene increased the tumorigenic potential of glioma cells through the PDK1/AKT and PAK/LIMK pathways. Taken together, we identify SRSF1 as an important oncodriver that integrates AS control of MYO1B into promotion of gliomagenesis and represents a potential prognostic biomarker and target for glioma therapy.

Authors

Xuexia Zhou, Run Wang, Xuebing Li, Lin Yu, Dan Hua, Cuiyun Sun, Cuijuan Shi, Wenjun Luo, Chun Rao, Zhendong Jiang, Ying Feng, Qian Wang, Shizhu Yu

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Figure 4

Validation and motif discovery of SRSF1-mediated AS in GBM cells.

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Validation and motif discovery of SRSF1-mediated AS in GBM cells. (A and...
(A and B) RT-PCR validation of SRSF1-affected AS events. Representative images from 3 independent experiments are presented. The structure of each PCR product is indicated schematically on the right. Alternative exons/introns affected by SRSF1 are painted in orange. The 4 lanes for GOLGA4 (B) are on the same gel but noncontiguous. The percentage of total products that were exon or intron inclusion products (in%) are provided below each gel. (C) Left: Flowchart of SRSF1 motif discovery from the RNA-Seq data. Right: The sum of the log2-transformed fold change (FC) of the GA-rich 6-mers overrepresented within the 5 regions around the regulated cassette exons is compared with that around the control cassette exons. The red line represents SRSF1-mediated cassette exon activation, and the blue line represents SRSF1-mediated cassette exon repression. Potential SRSF1 motifs derived from the 6-mers overrepresented in the activated or repressed cassette exons are also given.