The RNA-binding protein SERBP1 functions as a novel oncogenic factor in glioblastoma by bridging cancer metabolism and epigenetic regulation
| Autor: | Fabiana Marcelino Meliso, Anne Jenseit, Caihong Yi, Sarah Klinnert, Kevin C.H. Ha, Yogesh K. Gupta, Aleksandra Gruslova, Fanny Georgi, Franziska K. Lorbeer, Talia Delambre, Debashish Ray, Wei Qing Li, Timothy P. Hughes, Markus Flosbach, Luiz O. F. Penalva, Suzanne S. Burns, Xiufen Lei, Gabriela D A Guardia, Pedro A. F. Galante, Jennifer Chiou, Mei Qiao, Renu Pandey, Quaid Morris, Stefano Tiziani, Patrícia R. Araújo, Hong Zheng, Yi Ming Li, Erzsebet Kokovay, Andrew Brenner, Carolina Romero Sandoval, Adam Kosti |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
SERBP1 lcsh:QH426-470 medicine.medical_treatment Neurogenesis RNA-binding protein Biology One carbon cycle GBM Targeted therapy Epigenesis Genetic Epigenetic regulation 03 medical and health sciences Mice 0302 clinical medicine Glioma Gene expression Histone methylation medicine Animals Humans Epigenetics lcsh:QH301-705.5 030304 developmental biology 0303 health sciences Gene knockdown Brain Neoplasms Research RNA-Binding Proteins medicine.disease Prognosis Cancer metabolism United States lcsh:Genetics Phenotype lcsh:Biology (General) Cancer cell Cancer research Female Glioblastoma 030217 neurology & neurosurgery |
| Zdroj: | Genome Biology, Vol 21, Iss 1, Pp 1-32 (2020) Genome Biology |
| DOI: | 10.1186/s13059-020-02115-y |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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