SON drives oncogenic RNA splicing in glioblastoma by regulating PTBP1/PTBP2 switching and RBFOX2 activity

Jung-Hyun Kim, Kyuho Jeong, Jianfeng Li, James M. Murphy, Lana Vukadin, Joshua K. Stone, Alexander Richard, Johnny Tran, G. Yancey Gillespie, Erik K. Flemington, Robert W. Sobol (), Ssang-Teak Steve Lim () and Eun-Young Erin Ahn ()
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Jung-Hyun Kim: University of South Alabama
Kyuho Jeong: University of South Alabama
Jianfeng Li: University of South Alabama
James M. Murphy: University of South Alabama
Lana Vukadin: University of Alabama at Birmingham
Joshua K. Stone: University of South Alabama
Alexander Richard: University of South Alabama
Johnny Tran: University of South Alabama
G. Yancey Gillespie: University of Alabama at Birmingham
Erik K. Flemington: Tulane University School of Medicine, Tulane Cancer Center
Robert W. Sobol: University of South Alabama
Ssang-Teak Steve Lim: University of South Alabama
Eun-Young Erin Ahn: University of Alabama at Birmingham

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: Abstract While dysregulation of RNA splicing has been recognized as an emerging target for cancer therapy, the functional significance of RNA splicing and individual splicing factors in brain tumors is poorly understood. Here, we identify SON as a master regulator that activates PTBP1-mediated oncogenic splicing while suppressing RBFOX2-mediated non-oncogenic neuronal splicing in glioblastoma multiforme (GBM). SON is overexpressed in GBM patients and SON knockdown causes failure in intron removal from the PTBP1 transcript, resulting in PTBP1 downregulation and inhibition of its downstream oncogenic splicing. Furthermore, SON forms a complex with hnRNP A2B1 and antagonizes RBFOX2, which leads to skipping of RBFOX2-targeted cassette exons, including the PTBP2 neuronal exon. SON knockdown inhibits proliferation and clonogenicity of GBM cells in vitro and significantly suppresses tumor growth in orthotopic xenografts in vivo. Collectively, our study reveals that SON-mediated RNA splicing is a GBM vulnerability, implicating SON as a potential therapeutic target in brain tumors.

Date: 2021
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DOI: 10.1038/s41467-021-25892-x

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