The WWOX gene in brain development and pathology

Abstract

Shortly after its discovery in 2000, WWOX was hailed as a tumor suppressor gene. In subsequent years of research, this function was confirmed indisputably. Majority of tumors show high rate of loss of heterozygosity and decreased expression of WWOX. Nevertheless, over the years, the range of its known functions, at the cellular, organ and system levels, has expanded to include metabolism and endocrine system control and CNS differentiation and functioning. Despite of its function as a tumor suppressor gene, WWOX genetic alternations were found in a number of metabolic and neural diseases. A lack of WWOX protein as a consequence of germline mutations results in brain development disturbances and malfunctions. Impact statement WW domain-containing oxidoreductase encoded by the WWOX gene is a transcription regulator and a key player in a number of cellular and biological processes such as tumor suppression, cell proliferation, apoptosis induction, steroid metabolism, and central nervous system development. This review provides a comprehensive summary of currently known roles and discusses the importance of WWOX gene for CNS development and functioning.

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

“…GBM is also affected by WWOX, a cytoskeleton-related protein that interacts with ezrin, dystroglycan, or GSK−3β; it also influences on expression of DCLK, NEFL, NEFM, and MAP2/4/6 genes. As a tumor suppressor, it is lost in nearly a quarter of gliomas through a LOH event [22,23,26]. This study is the first to evaluate the role of WWOX in cytoskeleton dynamics of glioblastoma.…”

“…Its role in various metabolic disorders [20] or in cancer metabolism [21] was previously reported. Recently, our comprehensive review summarized the current knowledge about WWOX in the central nervous system (CNS), including brain tumors, i.e., astrocytoma, neuroblastoma, and glioblastoma [22]. For GBM, it has been found that WWOX downregulation may be a result of promoter hypermethylation or loss of heterozygosity (LOH); the latter is related to tumor progression and contributes to 20% of gliomas [22].…”

“…Recently, our comprehensive review summarized the current knowledge about WWOX in the central nervous system (CNS), including brain tumors, i.e., astrocytoma, neuroblastoma, and glioblastoma [22]. For GBM, it has been found that WWOX downregulation may be a result of promoter hypermethylation or loss of heterozygosity (LOH); the latter is related to tumor progression and contributes to 20% of gliomas [22]. Determining the role of WWOX in GBM is thought to be in the initial state [19]; hence, profound research is needed, especially in the cytoskeleton-related context, which remains enigmatic.…”

WWOX Loses the Ability to Regulate Oncogenic AP-2γ and Synergizes with Tumor Suppressor AP-2α in High-Grade Bladder Cancer

“…Further gene ontology on DEGs revealed that processes related to cancer hallmarks were frequently annotated; namely, cell cycle, proliferation, apoptosis, ECM organization, angiogenesis, EMT or migration. Many pathways appeared in at least three comparisons; MAPK, TGFβ, WNT, NOTCH or ERBB signaling were found to be dependent on WWOX, AP-2α and AP-2γ, i.e., MAPK [78][79][80], TGFβ [80][81][82], WNT [83,84], NOTCH [85][86][87] and ERBB [88,89]. Since WWOX is considered a global gene expression modulator [62] and both AP-2 transcription factors regulate thousands of genes and biological processes via specific pathways [79], it was foreseeable that changes in their expression affect cellular events at the broad scale.…”

WWOX-Related Neurodevelopmental Disorders: Models and Future Perspectives

“…The WW domain-containing oxidoreductase (WWOX) gene is gaining increasing attention for its possible role in both normal central nervous system (CNS) development, and its involvement in neurological diseases [2][3][4][5][6][7][8][9]. The WWOX gene was first discovered in the early 2000s due to its colocalization in the chromosomal common fragile site (CFS) FRA16D associated with cancer [10], which in turn led to thorough investigation of its role in tumor suppression, DNA damage response, metabolism, and cellular homeostasis, among other functions [11][12][13][14][15].…”