Antineoplastic Nature of WWOX in Glioblastoma Is Mainly a Consequence of Reduced Cell Viability and Invasion

SIMPLE SUMMARY: WWOX encodes a protein whose deficiency severely impacts brain development. Therefore, the impact of this tumor suppressor on brain tumors should also be investigated, particularly so as its nature has scarcely been elucidated in regard to the most common malignant brain cancer, i.e., glioblastoma. Unlike most of the current research, this study took advantage of several glioblastoma cell lines and biological assays to determine the main processes by which WWOX exhibits anticancer properties in glioblastoma. In the majority of the included cellular models, WWOX was found to intensify apoptosis, suppress cell viability, diminish adhesion to the extracellular matrix, decrease the quantity of colonies, and reduce invasiveness. Some discrepancies in the impacts on tumor proliferation and growth were noted and these were explained using bioinformatics tools. Nevertheless, WWOX inhibited glioblastoma viability and invasiveness independently of the cellular model. This is valuable to the scientific community as it guides the pursuit of research directions that can entail the development of relevant anticancer approaches, eventually leading to solutions similar to the WWOX gene therapy that is now under investigation for its usefulness in WWOX-related epileptic encephalopathy. ABSTRACT: Following the discovery of WWOX, research has moved in many directions, including the role of this putative tumor suppressor in the central nervous system and related diseases. The task of determining the nature of WWOX in glioblastoma (GBM) is still considered to be at the initial stage; however, the influence of this gene on the GBM malignant phenotype has already been reported. Because most of the available in vitro research does not consider several cellular GBM models or a wide range of investigated biological assays, the present study aimed to determine the main processes by which WWOX exhibits anticancer properties in GBM, while taking into account the phenotypic heterogeneity between cell lines. Ectopic WWOX overexpression was studied in T98G, DBTRG-05MG, U251MG, and U87MG cell lines that were compared with the use of assays investigating cell viability, proliferation, apoptosis, adhesion, clonogenicity, three-dimensional and anchorage-independent growth, and invasiveness. Observations presenting the antineoplastic properties of WWOX were consistent for T98G, U251MG, and U87MG. Increased proliferation and tumor growth were noted in WWOX-overexpressing DBTRG-05MG cells. A possible explanation for this, arrived at via bioinformatics tools, was linked to the TARDBP transcription factor and expression differences of USP25 and CPNE2 that regulate EGFR surface abundance. Collectively, and despite various cell line-specific circumstances, WWOX exhibits its anticancer nature mainly via a reduction of cell viability and invasiveness of glioblastoma.