The RNA-binding protein SERBP1 functions as a novel oncogenic factor in glioblastoma by bridging cancer metabolism and epigenetic regulation.

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  • Additional Information
    • Source:
      Publisher: BioMed Central Ltd Country of Publication: England NLM ID: 100960660 Publication Model: Electronic Cited Medium: Internet ISSN: 1474-760X (Electronic) Linking ISSN: 14747596 NLM ISO Abbreviation: Genome Biol Subsets: MEDLINE
    • Publication Information:
      Publication: London, UK : BioMed Central Ltd
      Original Publication: London : Genome Biology Ltd., c2000-
    • Subject Terms:
      Brain Neoplasms/*metabolism ; Glioblastoma/*metabolism ; RNA-Binding Proteins/*metabolism; Animals ; Brain Neoplasms/etiology ; Brain Neoplasms/mortality ; Brain Neoplasms/therapy ; Epigenesis, Genetic ; Female ; Glioblastoma/etiology ; Glioblastoma/mortality ; Glioblastoma/therapy ; Humans ; Male ; Mice ; Neurogenesis ; Phenotype ; Prognosis ; United States/epidemiology
    • Abstract:
      Background: RNA-binding proteins (RBPs) function as master regulators of gene expression. Alterations in RBP expression and function are often observed in cancer and influence critical pathways implicated in tumor initiation and growth. Identification and characterization of oncogenic RBPs and their regulatory networks provide new opportunities for targeted therapy.
      Results: We identify the RNA-binding protein SERBP1 as a novel regulator of glioblastoma (GBM) development. High SERBP1 expression is prevalent in GBMs and correlates with poor patient survival and poor response to chemo- and radiotherapy. SERBP1 knockdown causes delay in tumor growth and impacts cancer-relevant phenotypes in GBM and glioma stem cell lines. RNAcompete identifies a GC-rich region as SERBP1-binding motif; subsequent genomic and functional analyses establish SERBP1 regulation role in metabolic routes preferentially used by cancer cells. An important consequence of these functions is SERBP1 impact on methionine production. SERBP1 knockdown decreases methionine levels causing a subsequent reduction in histone methylation as shown for H3K27me3 and upregulation of genes associated with neurogenesis, neuronal differentiation, and function. Further analysis demonstrates that several of these genes are downregulated in GBM, potentially through epigenetic silencing as indicated by the presence of H3K27me3 sites.
      Conclusions: SERBP1 is the first example of an RNA-binding protein functioning as a central regulator of cancer metabolism and indirect modulator of epigenetic regulation in GBM. By bridging these two processes, SERBP1 enhances glioma stem cell phenotypes and contributes to GBM poorly differentiated state.
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    • Grant Information:
      R01 HG006015 United States HG NHGRI NIH HHS; 2R01 HG006015 United States NH NIH HHS
    • Contributed Indexing:
      Keywords: Cancer metabolism; Epigenetic regulation; GBM; One carbon cycle; RNA-binding protein; SERBP1
    • Accession Number:
      0 (RNA-Binding Proteins)
      0 (SERBP1 protein, human)
    • Publication Date:
      Date Created: 20200809 Date Completed: 20210708 Latest Revision: 20240329
    • Publication Date:
      20240329
    • Accession Number:
      PMC7412812
    • Accession Number:
      10.1186/s13059-020-02115-y
    • Accession Number:
      32762776