Journal Article

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

Li, Yi-Ming, Kosti, Adam, Georgi, Fanny, Kokovay, Erzsebet, Hughes, Timothy R., Tiziani, Stefano, Yi, Caihong, Burns, Suzanne S., Lorbeer, Franziska K., Pandey, Renu, Brenner, Andrew, Galante, Pedro A. F., Chiou, Jennifer, Klinnert, Sarah, Delambre, Talia, Gruslova, Aleksandra, de Araujo, Patricia Rosa, Gupta, Yogesh K., Morris, Quaid D., Flosbach, Markus, Qiao, Mei, Sandoval, Carolina Romero, Li, Wei-Qing, Jenseit, Anne, Penalva, Luiz O. F., Lei, Xiufen, Ha, Kevin, Ray, Debashish, Meliso, Fabiana, Guardia, Gabriela D. A., Zheng, Hong

2020

Overview

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.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Animal Genetics and Genomics / Animals / Apoptosis / Bioinformatics / Biomedical and Life Sciences / Brain cancer / Brain Neoplasms - etiology / Brain Neoplasms - metabolism / Brain Neoplasms - mortality / Brain Neoplasms - therapy / Cancer / Cancer Evolution and Metastasis / Cancer metabolism / Cancer therapies / Cell adhesion & migration / Chemotherapy / CRISPR / DNA methylation / Epigenesis, Genetic / Epigenetic regulation / Epigenetics / Evolutionary Biology / Female / GBM / Gene expression / Genes / genome / Genomes / genomics / Glioblastoma / Glioblastoma - etiology / Glioblastoma - metabolism / Glioblastoma - mortality / Glioblastoma - therapy / Glioma / Glioma cells / histones / Human Genetics / Humans / Kinases / Life Sciences / Male / Medical prognosis / Metabolism / Metastasis / Methionine / methylation / Mice / Microbial Genetics and Genomics / Nervous system / Neurogenesis / Neuromuscular diseases / neurons / One carbon cycle / Patients / Phenotype / Phenotypes / Plant Genetics and Genomics / Prognosis / Prostate cancer / Proteins / Radiation therapy / radiotherapy / Ribonucleic acid / RNA / RNA-binding protein / RNA-binding proteins / RNA-Binding Proteins - metabolism / SERBP1 / Stem cells / Tumorigenesis / United States - epidemiology