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

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

doi:10.1186/s13059-020-02115-y

Abstract

BackgroundRNA-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.ResultsWe 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.ConclusionsSERBP1 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.

Highlights

RNA-binding proteins (RBPs) function as master regulators of gene expression
SERBP1 is a novel prognostic marker in GBM We evaluated the role of SERBP1 as an oncogenic factor in glioma/GBM and its potential impact on patient survival and response to therapy
We observed that SERBP1 displays increased levels of expression in 25 tumor types when compared to normal tissue (Additional File 1: Fig. S1B) and data in the R2 database indicated that high SERBP1 expression is associated with poor prognosis in the cases of neuroblastoma, pancreatic adenocarcinoma, bladder urothelial carcinoma, cervical squamous cell carcinoma, and sarcomas (Additional File 1: Fig. S1C)

Summary

Introduction

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. In this respect, The Cancer Genome Atlas (TCGA) has produced an extensive transcriptomic map, identified prevalent chromosomal alterations, and defined important GBM driver mutations [1]. The Cancer Genome Atlas (TCGA) has produced an extensive transcriptomic map, identified prevalent chromosomal alterations, and defined important GBM driver mutations [1] This knowledge has improved molecular classification, but far, therapeutic strategies based on these findings have not yielded a major breakthrough. Studies on RNA-binding proteins (RBPs) that regulate these processes have the potential to expand our knowledge of GBM signaling and open up new avenues for therapy

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