<i>WWOX,</i> the chromosomal fragile site <i>FRA16D</i> spanning gene: Its role in metabolism and contribution to cancer

Richards, Robert I.; Choo, Amanda; Lee, Cheng Shoou; Dayan, Sonia; O’Keefe, Louise V.

doi:10.1177/1535370214565990

Cited by 24 publications

(28 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A genetic variant of the WWOX locus (CNV-67048), which is associated with reduced WWOX expression, has been recently correlated with predisposition to lung cancer and gliomas 52 53 54 . These results suggest that WWOX posses pleiotropic functions affecting metabolism, nervous system as well as cancer development 55 56 57 . The prevalence of one phenotype over the other could likely be related to context (e.g.…”

Section: Discussionmentioning

confidence: 87%

Tumor Suppressor WWOX inhibits osteosarcoma metastasis by modulating RUNX2 function

Mare

Aqeilan

2015

Sci Rep

View full text Add to dashboard Cite

Osteosarcoma (OS) is among the most frequently occurring primary bone tumors, primarily affecting adolescents and young adults. This malignant osteoid forming tumor is characterized by its metastatic potential, mainly to lungs. We recently demonstrated that WW domain-containing oxidoreductase (WWOX) is frequently inactivated in human OS and that WWOX restoration in WWOX-negative OS cells suppresses tumorigenicity. Of note, WWOX levels are reduced in paired OS samples of post-treatment metastastectomies as compared to pre-treatment biopsies suggesting that decreased WWOX levels are associated with a more aggressive phenotype at the metastatic site. Nevertheless, little is known about WWOX function in OS metastasis. Here, we investigated the role of tumor suppressor WWOX in suppressing pulmonary OS metastasis both in vitro and in vivo. We demonstrated that ectopic expression of WWOX in OS cells, HOS and LM-7, inhibits OS invasion and cell migration in vitro. Furthermore, WWOX expression reduced tumor burden in vivo and inhibited metastases’ seeding and colonization. Mechanistically, WWOX function is associated with reduced levels of RUNX2 metastatic target genes implicated in adhesion and motility. Our results suggest that WWOX plays a critical role in determining the aggressive phenotype of OS, and its expression could be an attractive therapeutic target to combat this devastating adolescent disease.

show abstract

Section: Discussionmentioning

confidence: 87%

Tumor Suppressor WWOX inhibits osteosarcoma metastasis by modulating RUNX2 function

Mare

Aqeilan

2015

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Human WWOX gene has 1.1 million bases and is located on a chromosomal common fragile site 16q23 or FRA16D . High frequency of loss of heterozygosity (LOH) of WWOX gene at approximately 30–50% levels has been shown in many types of cancer cells (Aqeilan and Croce, 2007; Chang et al, 2007; Del Mare et al, 2009; Gardenswartz and Aqeilan, 2014; Abu-Remaileh et al, 2015; Chang, 2015; Chang et al, 2015; Richards et al, 2015; Schrock and Huebner, 2015). Mutation of WWOX gene in breast cancer occurs frequently at exons 4–9 (Ekizoglu et al, 2012).…”

Section: Tumor Suppressor Wwox Is Anchored On the Cell Membrane By Hymentioning

confidence: 99%

HYAL-2–WWOX–SMAD4 Signaling in Cell Death and Anticancer Response

Hsu

Chiang

Sze

et al. 2016

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Hyaluronidase HYAL-2 is a membrane-anchored protein and also localizes, in part, in the lysosome. Recent study from animal models revealed that both HYAL-1 and HYAL-2 are essential for the metabolism of hyaluronan (HA). Hyal-2 deficiency is associated with chronic thrombotic microangiopathy with hemolytic anemia in mice due to over accumulation of high molecular size HA. HYAL-2 is essential for platelet generation. Membrane HYAL-2 degrades HA bound by co-receptor CD44. Also, in a non-canonical signal pathway, HYAL-2 serves as a receptor for transforming growth factor beta (TGF-β) to signal with downstream tumor suppressors WWOX and SMAD4 to control gene transcription. When SMAD4 responsive element is overly driven by the HYAL-2–WWOX–SMAD4 signaling complex, cell death occurs. When rats are subjected to traumatic brain injury, over accumulation of a HYAL-2–WWOX complex occurs in the nucleus to cause neuronal death. HA induces the signaling of HYAL-2–WWOX–SMAD4 and relocation of the signaling complex to the nucleus. If the signaling complex is overexpressed, bubbling cell death occurs in WWOX-expressing cells. In addition, a small synthetic peptide Zfra (zinc finger-like protein that regulates apoptosis) binds membrane HYAL-2 of non-T/non-B spleen HYAL-2+ CD3− CD19− Z lymphocytes and activates the cells to generate memory anticancer response against many types of cancer cells in vivo. Whether the HYAL-2–WWOX–SMAD4 signaling complex is involved is discussed. In this review and opinion article, we have updated the current knowledge of HA, HYAL-2 and WWOX, HYAL-2–WWOX–SMAD4 signaling, bubbling cell death, and Z cell activation for memory anticancer response.

show abstract

“…The FRA16D CFS is located within the WW domain containing oxidoreductase ( WWOX ) gene (Bednarek et al, ; Ried et al, ). Phylogenetic analyses have revealed that a WWOX ortholog is found in organisms as evolutionarily distinct as humans and sea sponge, indicating that WWOX likely performs a unique and primary biological function (Richards et al, ). Reduced levels of full‐length WWOX have been reported in multiple types of cancers (Paige et al, ; Lewandowska et al, ; Gardenswartz and Aqeilan, ; Schrock and Huebner, ) and correlate with poorer prognosis (Pluciennik et al, ; Zelazowski et al, ).…”

Section: Introductionmentioning

confidence: 99%

Tumor suppressor WWOX moderates the mitochondrial respiratory complex

Choo

O’Keefe

Lee

et al. 2015

Genes Chromosomes & Cancer

Self Cite

View full text Add to dashboard Cite

Fragile site FRA16D exhibits DNA instability in cancer, resulting in diminished levels of protein from the WWOX gene that spans it. WWOX suppresses tumor growth by an undefined mechanism. WWOX participates in pathways involving aerobic metabolism and reactive oxygen species. WWOX comprises two WW domains as well as a short-chain dehydrogenase/reductase enzyme. Herein is described an in vivo genetic analysis in Drosophila melanogaster to identify functional interactions between WWOX and metabolic pathways. Altered WWOX levels modulate variable cellular outgrowths caused by genetic deficiencies of components of the mitochondrial respiratory complexes. This modulation requires the enzyme active site of WWOX, and the defective respiratory complex-induced cellular outgrowths are mediated by reactive oxygen species, dependent upon the Akt pathway and sensitive to levels of autophagy and hypoxia-inducible factor. WWOX is known to contribute to homeostasis by regulating the balance between oxidative phosphorylation and glycolysis. Reduction of WWOX levels results in diminished ability to respond to metabolic perturbation of normal cell growth. Thus, the ability of WWOX to facilitate escape from mitochondrial damage-induced glycolysis (Warburg effect) is, therefore, a plausible mechanism for its tumor suppressor activity.

show abstract

WWOX, the chromosomal fragile site FRA16D spanning gene: Its role in metabolism and contribution to cancer

Cited by 24 publications

References 41 publications

Tumor Suppressor WWOX inhibits osteosarcoma metastasis by modulating RUNX2 function

Tumor Suppressor WWOX inhibits osteosarcoma metastasis by modulating RUNX2 function

HYAL-2–WWOX–SMAD4 Signaling in Cell Death and Anticancer Response

Tumor suppressor WWOX moderates the mitochondrial respiratory complex

Contact Info

Product

Resources

About