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

Author

Listed:
  • Jung-Hyun Kim

    (University of South Alabama
    University of South Alabama)

  • Kyuho Jeong

    (University of South Alabama)

  • Jianfeng Li

    (University of South Alabama
    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
    University of South Alabama)

  • Ssang-Teak Steve Lim

    (University of South Alabama)

  • Eun-Young Erin Ahn

    (University of Alabama at Birmingham
    University of Alabama at Birmingham)

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.

Suggested Citation

  • 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, 2021. "SON drives oncogenic RNA splicing in glioblastoma by regulating PTBP1/PTBP2 switching and RBFOX2 activity," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25892-x
    DOI: 10.1038/s41467-021-25892-x
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    Cited by:

    1. Maciej Bak & Erik Nimwegen & Ian U. Kouzel & Tamer Gur & Ralf Schmidt & Mihaela Zavolan & Andreas J. Gruber, 2024. "MAPP unravels frequent co-regulation of splicing and polyadenylation by RNA-binding proteins and their dysregulation in cancer," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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