Elucidation of the genetic and epigenetic landscape alterations in RNA binding proteins in glioblastoma

Shruti Bhargava,Kumaravel Somasundaram,Vikas Patil,Kulandaivelu Mahalingam

doi:10.18632/oncotarget.14287

Shruti Bhargava, Kumaravel Somasundaram + Show 2 more

Open Access

https://doi.org/10.18632/oncotarget.14287

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Abstract

RNA binding proteins (RBPs) have been implicated in cancer development. An integrated bioinformatics analysis of RBPs (n = 1756) in various datasets (n = 11) revealed several genetic and epigenetically altered events among RBPs in glioblastoma (GBM). We identified 13 mutated and 472 differentially regulated RBPs in GBM samples. Mutations in AHNAK predicted poor prognosis. Copy number variation (CNV), DNA methylation and miRNA targeting contributed to RBP differential regulation. Two sets of differentially regulated RBPs that may be implicated in initial astrocytic transformation and glioma progression were identified. We have also identified a four RBP (NOL3, SUCLG1, HERC5 and AFF3) signature, having a unique expression pattern in glioma stem-like cells (GSCs), to be an independent poor prognostic indicator in GBM. RBP risk score derived from the signature also stratified GBM into low-risk and high-risk groups with significant survival difference. Silencing NOL3, SUCLG1 and HERC5 inhibited GSC maintenance. Gene set enrichment analysis of differentially regulated genes between high-risk and low-risk underscored the importance of inflammation, EMT and hypoxia in high-risk GBM. Thus, we provide a comprehensive overview of genetic and epigenetic regulation of RBPs in glioma development and progression.

Highlights

Glioblastoma (GBM) is one of the most lethal primary brain tumors
Integrated genome analysis reveals genetic and epigenetic alterations in RNA binding proteins (RBPs) in glioblastoma To elucidate the various aspects of RBP biology in GBM, we derived a comprehensive list of 1756 RBPs (Supplementary Table 1) from Castello et al, 2012 and Gerstberger et al, 2014 [8, 9] for further investigation
Using these approaches we identified deleterious mutations and their association with prognosis, RBPs that are relevant to glia transformation and progression and that are uniquely expressed in glioma stem-like cells (GSC)

Summary

Introduction

Glioblastoma (GBM) is one of the most lethal primary brain tumors. In spite of several improvements in therapeutic modalities, the median survival remains low at 14-16 months [1]. Numerous studies often indicate a lack of significant correlation between the transcript and protein levels in cells [5]. These observations led to the belief that additional processes may play important role in affecting the cellular pool of proteins translated from their respective transcripts. This paradox can be further explained by the identification of post transcriptional regulatory check points which contribute immensely to the protein level regulation. These check points mainly consist of regulation mediated by non-coding RNAs (miRNAs and lncRNAs) and the RNA binding proteins [6]

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