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

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

  • Genome Biol. 2020 Aug 6;21(1):195. doi: 10.1186/s13059-020-02115-y.
Adam Kosti 1 2,  Patricia Rosa de Araujo 1 2,  Wei-Qing Li 1 3,  Gabriela D A Guardia 4,  Jennifer Chiou 5,  Caihong Yi 1,  Debashish Ray 6,  Fabiana Meliso 4,  Yi-Ming Li 3,  Talia Delambre 1,  Mei Qiao 1,  Suzanne S Burns 1,  Franziska K Lorbeer 1,  Fanny Georgi 1,  Markus Flosbach 1,  Sarah Klinnert 1,  Anne Jenseit 1,  Xiufen Lei 1,  Carolina Romero Sandoval 1,  Kevin Ha 6,  Hong Zheng 6,  Renu Pandey 1,  Aleksandra Gruslova 7,  Yogesh K Gupta 1,  Andrew Brenner 8,  Erzsebet Kokovay 2,  Timothy R Hughes 6 9 10,  Quaid D Morris 6 9 11,  Pedro A F Galante 12,  Stefano Tiziani 13,  Luiz O F Penalva 14 15
Affiliations

Affiliations

  • 1 Children's Cancer Research Institute, UT Health San Antonio, San Antonio, TX, 78229, USA.
  • 2 Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, 78229, USA.
  • 3 Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China.
  • 4 Centro de Oncologia Molecular, Hospital Sírio-Libanês, São Paulo, São Paulo, 01309-060, Brazil.
  • 5 Department of Nutritional Sciences, Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, Austin, TX, 78712, USA.
  • 6 Donnelly Centre, University of Toronto, Toronto, ON, M5S 3E1, Canada.
  • 7 Department of Medicine, UT Health San Antonio, San Antonio, TX, 78229, USA.
  • 8 Mays Cancer Center, UT Health San Antonio, San Antonio, TX, 78229, USA.
  • 9 Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
  • 10 Canadian Institute for Advanced Research, MaRS Centre, West Tower, 661 University Avenue, Suite 505, Toronto, ON, M5G 1M1, Canada.
  • 11 Department of Computer Science, University of Toronto, Toronto, ON, M5T 3A1, Canada.
  • 12 Centro de Oncologia Molecular, Hospital Sírio-Libanês, São Paulo, São Paulo, 01309-060, Brazil. pgalante@mochsl.org.br.
  • 13 Department of Nutritional Sciences, Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, Austin, TX, 78712, USA. tiziani@austin.utexas.edu.
  • 14 Children's Cancer Research Institute, UT Health San Antonio, San Antonio, TX, 78229, USA. penalva@uthscsa.edu.
  • 15 Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, 78229, USA. penalva@uthscsa.edu.
PMID: 32762776 DOI: 10.1186/s13059-020-02115-y
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.

Keywords

Cancer metabolism; Epigenetic regulation; GBM; One carbon cycle; RNA-binding protein; SERBP1.

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