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WWOX: A Fragile Tumor Suppressor with Pleotropic Functions
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WWOX: A Fragile Tumor Suppressor with Pleotropic Functions

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 21378

Special Issue Editor

Prof. Rami Aqeilan

E-Mail Website
Guest Editor
Division of Cell biology, Immunology and Cancer Research, Hebrew University-Hadassah Medical School, Lautenberg Center for Immunology and Cancer Research, Jerusalem 91120, Israel
Interests: genomic Instability; DDR signalling; DSBs; Common Fragile Sites; osteosarcoma; triple-negative breast cancer; early-onset epilepsy

Special Issue Information

Dear Colleagues,

Genomic instability is a hallmark of all cancers. Uncovering drivers (trans) and genomic regions (cis) that are directly involved in genomic instability has been a central theme in the biology of cancer. The role of common fragile sites (CFSs) (cis) and their gene products (trans) has been controversial in this context. Genomic aberrations in CFSs have been known for decades as ‘hotspots’ for large deletions and copy number variations in cancer. In fact, the most recurrent allelic imbalances in human cancer specimens and cell lines overlap with large genes and CFSs. This notion has led to the assumption that perturbations in CFSs could be secondary events that do not directly drive the multistep carcinogenesis process. On the other hand, cumulative evidence implies otherwise as several gene products of CFSs have been directly linked with tumor suppression. One prominent example is perturbations in the WW domain-containing oxidoreductase (WWOX) gene, spanning FRA16D, and one of the commonly deleted genes/loci in human tumors. Intriguingly, the WWOX protein has been shown to modulate key signaling pathways such as WNT and TGFβ, the DNA damage response (DDR) signaling, cellular metabolism and more. Studying this multifaceted role of WWOX and other gene products opf CFSs have been a central theme of several research laboratories around the world. 

The current Special Issue aims to review the most recent advances in WWOX biology, its key roles in tumor suppression, and its emerging roles in neuropathy and metabolism. Our goal is to highlight the central functions of WWOX and shed light on its intriguing location in active CFSs. With the latter, we aim to also promote discussion on recent progress and roles of CFSs and their gene products not only in cancer but also other human diseases. 

Prof. Rami Aqeilan
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • common fragile sites
  • WWOX
  • FHIT
  • tumor suppression
  • genomic instability
  • DDR signaling
  • replication stress
  • homeostasis
  • cancer
  • neurological disorders
  • metabolic disorders

Published Papers (6 papers)

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Review

19 pages, 5478 KiB  
Review
WWOX Controls Cell Survival, Immune Response and Disease Progression by pY33 to pS14 Transition to Alternate Signaling Partners
by Tsung-Yun Liu, Ganesan Nagarajan, Ming-Fu Chiang, Shenq-Shyang Huang, Tzu-Chia Lin, Yu-An Chen, Chun-I Sze and Nan-Shan Chang
Cells 2022, 11(14), 2137; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11142137 - 07 Jul 2022
Cited by 1 | Viewed by 2336
Abstract
Tumor suppressor WWOX inhibits cancer growth and retards Alzheimer’s disease (AD) progression. Supporting evidence shows that the more strongly WWOX binds intracellular protein partners, the weaker is cancer cell growth in vivo. Whether this correlates with retardation of AD progression is unknown. Two [...] Read more.
Tumor suppressor WWOX inhibits cancer growth and retards Alzheimer’s disease (AD) progression. Supporting evidence shows that the more strongly WWOX binds intracellular protein partners, the weaker is cancer cell growth in vivo. Whether this correlates with retardation of AD progression is unknown. Two functional forms of WWOX exhibit opposite functions. pY33-WWOX is proapoptotic and anticancer, and is essential for maintaining normal physiology. In contrast, pS14-WWOX is accumulated in the lesions of cancers and AD brains, and suppression of WWOX phosphorylation at S14 by a short peptide Zfra abolishes cancer growth and retardation of AD progression. In parallel, synthetic Zfra4-10 or WWOX7-21 peptide strengthens the binding of endogenous WWOX with intracellular protein partners leading to cancer suppression. Indeed, Zfra4-10 is potent in restoring memory loss in triple transgenic mice for AD (3xTg) by blocking the aggregation of amyloid beta 42 (Aβ42), enhancing degradation of aggregated proteins, and inhibiting activation of inflammatory NF-κB. In light of the findings, Zfra4-10-mediated suppression of cancer and AD is due, in part, to an enhanced binding of endogenous WWOX and its binding partners. In this perspective review article, we detail the molecular action of WWOX in the HYAL-2/WWOX/SMAD4 signaling for biological effects, and discuss WWOX phosphorylation forms in interacting with binding partners, leading to suppression of cancer growth and retardation of AD progression. Full article
(This article belongs to the Special Issue WWOX: A Fragile Tumor Suppressor with Pleotropic Functions)
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30 pages, 2083 KiB  
Review
WWOX-Related Neurodevelopmental Disorders: Models and Future Perspectives
by Daniel J. Steinberg and Rami I. Aqeilan
Cells 2021, 10(11), 3082; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10113082 - 09 Nov 2021
Cited by 7 | Viewed by 3683
Abstract
The WW domain-containing oxidoreductase (WWOX) gene was originally discovered as a putative tumor suppressor spanning the common fragile site FRA16D, but as time has progressed the extent of its pleiotropic function has become apparent. At present, WWOX is a major source [...] Read more.
The WW domain-containing oxidoreductase (WWOX) gene was originally discovered as a putative tumor suppressor spanning the common fragile site FRA16D, but as time has progressed the extent of its pleiotropic function has become apparent. At present, WWOX is a major source of interest in the context of neurological disorders, and more specifically developmental and epileptic encephalopathies (DEEs). This review article aims to introduce the many model systems used through the years to study its function and roles in neuropathies. Similarities and fundamental differences between rodent and human models are discussed. Finally, future perspectives and promising research avenues are suggested. Full article
(This article belongs to the Special Issue WWOX: A Fragile Tumor Suppressor with Pleotropic Functions)
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17 pages, 2984 KiB  
Review
WWOX and Its Binding Proteins in Neurodegeneration
by Che-Yu Hsu, Kuan-Ting Lee, Tzu-Yu Sun, Chun-I. Sze, Shenq-Shyang Huang, Li-Jin Hsu and Nan-Shan Chang
Cells 2021, 10(7), 1781; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10071781 - 14 Jul 2021
Cited by 10 | Viewed by 3456
Abstract
WW domain-containing oxidoreductase (WWOX) is known as one of the risk factors for Alzheimer’s disease (AD), a neurodegenerative disease. WWOX binds Tau via its C-terminal SDR domain and interacts with Tau phosphorylating enzymes ERK, JNK, and GSK-3β, and thereby limits AD progression. Loss [...] Read more.
WW domain-containing oxidoreductase (WWOX) is known as one of the risk factors for Alzheimer’s disease (AD), a neurodegenerative disease. WWOX binds Tau via its C-terminal SDR domain and interacts with Tau phosphorylating enzymes ERK, JNK, and GSK-3β, and thereby limits AD progression. Loss of WWOX in newborns leads to severe neural diseases and early death. Gradual loss of WWOX protein in the hippocampus and cortex starting from middle age may slowly induce aggregation of a protein cascade that ultimately causes accumulation of extracellular amyloid beta plaques and intracellular tau tangles, along with reduction in inhibitory GABAergic interneurons, in AD patients over 70 years old. Age-related increases in pS14-WWOX accumulation in the brain promotes neuronal degeneration. Suppression of Ser14 phosphorylation by a small peptide Zfra leads to enhanced protein degradation, reduction in NF-κB-mediated inflammation, and restoration of memory loss in triple transgenic mice for AD. Intriguingly, tumor suppressors p53 and WWOX may counteract each other in vivo, which leads to upregulation of AD-related protein aggregation in the brain and lung. WWOX has numerous binding proteins. We reported that the stronger the binding between WWOX and its partners, the better the suppression of cancer growth and reduction in inflammation. In this regard, the stronger complex formation between WWOX and partners may provide a better blockade of AD progression. In this review, we describe whether and how WWOX and partner proteins control inflammatory response and protein aggregation and thereby limit AD progression. Full article
(This article belongs to the Special Issue WWOX: A Fragile Tumor Suppressor with Pleotropic Functions)
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12 pages, 8547 KiB  
Review
Molecular Biology of the WWOX Gene That Spans Chromosomal Fragile Site FRA16D
by Cheng Shoou Lee, Amanda Choo, Sonia Dayan, Robert I. Richards and Louise V. O’Keefe
Cells 2021, 10(7), 1637; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10071637 - 29 Jun 2021
Cited by 6 | Viewed by 2429
Abstract
It is now more than 20 years since the FRA16D common chromosomal fragile site was characterised and the WWOX gene spanning this site was identified. In this time, much information has been discovered about its contribution to disease; however, the normal biological role [...] Read more.
It is now more than 20 years since the FRA16D common chromosomal fragile site was characterised and the WWOX gene spanning this site was identified. In this time, much information has been discovered about its contribution to disease; however, the normal biological role of WWOX is not yet clear. Experiments leading to the identification of the WWOX gene are recounted, revealing enigmatic relationships between the fragile site, its gene and the encoded protein. We also highlight research mainly using the genetically tractable model organism Drosophila melanogaster that has shed light on the integral role of WWOX in metabolism. In addition to this role, there are some particularly outstanding questions that remain regarding WWOX, its gene and its chromosomal location. This review, therefore, also aims to highlight two unanswered questions. Firstly, what is the biological relationship between the WWOX gene and the FRA16D common chromosomal fragile site that is located within one of its very large introns? Secondly, what is the actual substrate and product of the WWOX enzyme activity? It is likely that understanding the normal role of WWOX and its relationship to chromosomal fragility are necessary in order to understand how the perturbation of these normal roles results in disease. Full article
(This article belongs to the Special Issue WWOX: A Fragile Tumor Suppressor with Pleotropic Functions)
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15 pages, 1961 KiB  
Review
Molecular Functions of WWOX Potentially Involved in Cancer Development
by Karim Taouis, Keltouma Driouch, Rosette Lidereau and François Lallemand
Cells 2021, 10(5), 1051; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10051051 - 29 Apr 2021
Cited by 14 | Viewed by 2903
Abstract
The WW domain-containing oxidoreductase gene (WWOX) was cloned 21 years ago as a putative tumor suppressor gene mapping to chromosomal fragile site FRA16D. The localization of WWOX in a chromosomal region frequently altered in human cancers has initiated multiple current studies [...] Read more.
The WW domain-containing oxidoreductase gene (WWOX) was cloned 21 years ago as a putative tumor suppressor gene mapping to chromosomal fragile site FRA16D. The localization of WWOX in a chromosomal region frequently altered in human cancers has initiated multiple current studies to establish its role in this disease. All of this work suggests that WWOX, due to its ability to interact with a large number of partners, exerts its tumor suppressive activity through a wide variety of molecular actions that are mostly cell specific. Full article
(This article belongs to the Special Issue WWOX: A Fragile Tumor Suppressor with Pleotropic Functions)
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20 pages, 1549 KiB  
Review
Neurological Disorders Associated with WWOX Germline Mutations—A Comprehensive Overview
by Ehud Banne, Baraa Abudiab, Sara Abu-Swai, Srinivasa Rao Repudi, Daniel J. Steinberg, Diala Shatleh, Sarah Alshammery, Leszek Lisowski, Wendy Gold, Peter L. Carlen and Rami I. Aqeilan
Cells 2021, 10(4), 824; https://doi.org/10.3390/cells10040824 - 07 Apr 2021
Cited by 13 | Viewed by 5680
Abstract
The transcriptional regulator WW domain-containing oxidoreductase (WWOX) is a key player in a number of cellular and biological processes including tumor suppression. Recent evidence has emerged associating WWOX with non-cancer disorders. Patients harboring pathogenic germline bi-allelic WWOX variants have been described with the [...] Read more.
The transcriptional regulator WW domain-containing oxidoreductase (WWOX) is a key player in a number of cellular and biological processes including tumor suppression. Recent evidence has emerged associating WWOX with non-cancer disorders. Patients harboring pathogenic germline bi-allelic WWOX variants have been described with the rare devastating neurological syndromes autosomal recessive spinocerebellar ataxia 12 (SCAR12) (6 patients) and WWOX-related epileptic encephalopathy (DEE28 or WOREE syndrome) (56 patients). Individuals with these syndromes present with a highly heterogenous clinical spectrum, the most common clinical symptoms being severe epileptic encephalopathy and profound global developmental delay. Knowledge of the underlying pathophysiology of these syndromes, the range of variants of the WWOX gene and its genotype-phenotype correlations is limited, hampering therapeutic efforts. Therefore, there is a critical need to identify and consolidate all the reported variants in WWOX to distinguish between disease-causing alleles and their associated severity, and benign variants, with the aim of improving diagnosis and increasing therapeutic efforts. Here, we provide a comprehensive review of the literature on WWOX, and analyze the pathogenic variants from published and unpublished reports by collecting entries from the ClinVar, DECIPHER, VarSome, and PubMed databases to generate the largest dataset of WWOX pathogenic variants. We estimate the correlation between variant type and patient phenotype, and delineate the impact of each variant, and used GnomAD to cross reference these variants found in the general population. From these searches, we generated the largest published cohort of WWOX individuals. We conclude with a discussion on potential personalized medicine approaches to tackle the devastating disorders associated with WWOX mutations. Full article
(This article belongs to the Special Issue WWOX: A Fragile Tumor Suppressor with Pleotropic Functions)
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