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

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.

• Authors: 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, Eun-Young Erin Ahn
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 5551 (09 21 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 34548489 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2021. The Author(s).

Chemical References

• DNA-Binding Proteins
• Heterogeneous-Nuclear Ribonucleoprotein Group A-B
• Heterogeneous-Nuclear Ribonucleoproteins
• Minor Histocompatibility Antigens
• Nerve Tissue Proteins
• PTBP1 protein, human
• PTBP2 protein, human
• RBFOX2 protein, human
• RNA Splicing Factors
• RNA, Messenger
• RNA, Small Interfering
• Repressor Proteins
• SON protein, human
• Polypyrimidine Tract-Binding Protein

Topics

• Animals
• Brain Neoplasms (genetics, metabolism, mortality, pathology)
• Cell Cycle (genetics)
• Cell Line, Tumor
• Cell Proliferation
• DNA-Binding Proteins (antagonists & inhibitors, genetics, metabolism)
• Exons
• Gene Expression Regulation, Neoplastic
• Glioblastoma (genetics, metabolism, mortality, pathology)
• Heterogeneous-Nuclear Ribonucleoprotein Group A-B (genetics, metabolism)
• Heterogeneous-Nuclear Ribonucleoproteins (genetics, metabolism)
• Heterografts
• Humans
• Introns
• Mice
• Minor Histocompatibility Antigens (genetics, metabolism)
• Nerve Tissue Proteins (genetics, metabolism)
• Neuroglia (metabolism, pathology)
• Neurons (metabolism, pathology)
• Polypyrimidine Tract-Binding Protein (genetics, metabolism)
• RNA Splicing
• RNA Splicing Factors (genetics, metabolism)
• RNA, Messenger (genetics, metabolism)
• RNA, Small Interfering (genetics, metabolism)
• Repressor Proteins (genetics, metabolism)
• Signal Transduction
• Spheroids, Cellular (metabolism, pathology)
• Survival Analysis