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

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 spli...

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Autores principales: Kim, Jung-Hyun, Jeong, Kyuho, Li, Jianfeng, Murphy, James M., Vukadin, Lana, Stone, Joshua K., Richard, Alexander, Tran, Johnny, Gillespie, G. Yancey, Flemington, Erik K., Sobol, Robert W., Lim, Ssang-Teak Steve, Ahn, Eun-Young Erin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455679/
https://www.ncbi.nlm.nih.gov/pubmed/34548489
http://dx.doi.org/10.1038/s41467-021-25892-x
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author Kim, Jung-Hyun
Jeong, Kyuho
Li, Jianfeng
Murphy, James M.
Vukadin, Lana
Stone, Joshua K.
Richard, Alexander
Tran, Johnny
Gillespie, G. Yancey
Flemington, Erik K.
Sobol, Robert W.
Lim, Ssang-Teak Steve
Ahn, Eun-Young Erin
author_facet Kim, Jung-Hyun
Jeong, Kyuho
Li, Jianfeng
Murphy, James M.
Vukadin, Lana
Stone, Joshua K.
Richard, Alexander
Tran, Johnny
Gillespie, G. Yancey
Flemington, Erik K.
Sobol, Robert W.
Lim, Ssang-Teak Steve
Ahn, Eun-Young Erin
author_sort Kim, Jung-Hyun
collection PubMed
description 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.
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spelling pubmed-84556792021-10-07 SON drives oncogenic RNA splicing in glioblastoma by regulating PTBP1/PTBP2 switching and RBFOX2 activity Kim, Jung-Hyun Jeong, Kyuho Li, Jianfeng Murphy, James M. Vukadin, Lana Stone, Joshua K. Richard, Alexander Tran, Johnny Gillespie, G. Yancey Flemington, Erik K. Sobol, Robert W. Lim, Ssang-Teak Steve Ahn, Eun-Young Erin Nat Commun Article 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. Nature Publishing Group UK 2021-09-21 /pmc/articles/PMC8455679/ /pubmed/34548489 http://dx.doi.org/10.1038/s41467-021-25892-x Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Kim, Jung-Hyun
Jeong, Kyuho
Li, Jianfeng
Murphy, James M.
Vukadin, Lana
Stone, Joshua K.
Richard, Alexander
Tran, Johnny
Gillespie, G. Yancey
Flemington, Erik K.
Sobol, Robert W.
Lim, Ssang-Teak Steve
Ahn, Eun-Young Erin
SON drives oncogenic RNA splicing in glioblastoma by regulating PTBP1/PTBP2 switching and RBFOX2 activity
title SON drives oncogenic RNA splicing in glioblastoma by regulating PTBP1/PTBP2 switching and RBFOX2 activity
title_full SON drives oncogenic RNA splicing in glioblastoma by regulating PTBP1/PTBP2 switching and RBFOX2 activity
title_fullStr SON drives oncogenic RNA splicing in glioblastoma by regulating PTBP1/PTBP2 switching and RBFOX2 activity
title_full_unstemmed SON drives oncogenic RNA splicing in glioblastoma by regulating PTBP1/PTBP2 switching and RBFOX2 activity
title_short SON drives oncogenic RNA splicing in glioblastoma by regulating PTBP1/PTBP2 switching and RBFOX2 activity
title_sort son drives oncogenic rna splicing in glioblastoma by regulating ptbp1/ptbp2 switching and rbfox2 activity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455679/
https://www.ncbi.nlm.nih.gov/pubmed/34548489
http://dx.doi.org/10.1038/s41467-021-25892-x
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