PLEK2, RRM2, GCSH: A Novel WWOX-Dependent Biomarker Triad of Glioblastoma at the Crossroads of Cytoskeleton Reorganization and Metabolism Alterations.

Żaneta Kałuzińska,Damian Kołat,Elżbieta Płuciennik,Andrzej K Bednarek

doi:10.3390/cancers13122955

Abstract

Simple SummaryCytoskeleton reorganization affects the malignancy of glioblastoma. The WWOX gene is a tumor suppressor in glioblastoma and was found to modulate the cytoskeletal machinery in neural progenitor cells. To date, the role of this gene in the cytoskeleton or glioblastoma has been studied separately. Therefore, the purpose of this study was to investigate WWOX-dependent genes in glioblastoma and indicate cytoskeleton-related processes they are involved in. The most relevant WWOX-dependent genes were found to be PLEK2, RRM2, and GCSH, which have been proposed as novel biomarkers. Their biological functions suggest that there is an important link between cytoskeleton and metabolism, orchestrating tumor proliferation, metastasis, and resistance. Searching for such new therapeutic targets is important due to the constant lack of effective treatment for glioblastoma patients.Glioblastoma is one of the deadliest human cancers. Its malignancy depends on cytoskeleton reorganization, which is related to, e.g., epithelial-to-mesenchymal transition and metastasis. The malignant phenotype of glioblastoma is also affected by the WWOX gene, which is lost in nearly a quarter of gliomas. Although the role of WWOX in the cytoskeleton rearrangement has been found in neural progenitor cells, its function as a modulator of cytoskeleton in gliomas was not investigated. Therefore, this study aimed to investigate the role of WWOX and its collaborators in cytoskeleton dynamics of glioblastoma. Methodology on RNA-seq data integrated the use of databases, bioinformatics tools, web-based platforms, and machine learning algorithm, and the obtained results were validated through microarray data. PLEK2, RRM2, and GCSH were the most relevant WWOX-dependent genes that could serve as novel biomarkers. Other genes important in the context of cytoskeleton (BMP4, CCL11, CUX2, DUSP7, FAM92B, GRIN2B, HOXA1, HOXA10, KIF20A, NF2, SPOCK1, TTR, UHRF1, and WT1), metabolism (MTHFD2), or correlation with WWOX (COL3A1, KIF20A, RNF141, and RXRG) were also discovered. For the first time, we propose that changes in WWOX expression dictate a myriad of alterations that affect both glioblastoma cytoskeleton and metabolism, rendering new therapeutic possibilities.

Highlights

Amongst gliomas, the most common aggressive primary brain tumor is glioblastoma IDH wild-type (GBM), constituting more than a half of the tumors originating from glia or glial precursors [1,2]
Performing gene set enrichment analysis (GSEA) with the use of the selected cut-point confirmed the presence of gene sets such as BIOCARTA/KEGG/REACTOME canonical pathways; chemical and genetic perturbations (CGP); gene ontology (GO): biological processes (BP) and molecular function (MF); cancer gene neighborhoods (CGN); and oncogenic and immunologic signatures, hallmarks, and positional gene sets
GBM is affected by WW domain-containing oxidoreductase (WWOX), a cytoskeleton-related protein that interacts with ezrin, dystroglycan, or GSK−3β; it influences on expression of DCLK, NEFL, NEFM, and MAP2/4/6 genes

Summary

Introduction

The most common aggressive primary brain tumor is glioblastoma IDH wild-type (GBM), constituting more than a half of the tumors originating from glia or glial precursors [1,2]. WWOX can be summarized as a global modulator of transcription and an important regulator of differentiation and maintenance [18]; this is complemented with the prognostic relevance of WWOX [19]. Available data indicate that WW domain of WWOX collaborates, e.g., with dystroglycan, a transmembrane protein that interacts with utrophin and dystrophin, which communicate with actin [23]. Such finding proves the implication of WWOX in complex machinery involving both extracellular matrix (ECM) and cytoskeleton [23]. WWOX silencing changed the expression profile of genes (e.g., DCLK, NEFL, NEFM, MAP2/4/6) involved in the cytoskeleton organization of neural progenitor cells [18]

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