Opinion
WW domain-containing oxidoreductase: a candidate tumor suppressor

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Common fragile site gene WWOX encodes a candidate tumor suppressor WW domain-containing oxidoreductase. Alteration of this gene, along with dramatic downregulation of WWOX protein, is shown in the majority of invasive cancer cells. Ectopic WWOX exhibits proapoptotic and tumor inhibitory functions in vitro and in vivo, probably interacting with growth regulatory proteins p53, p73 and others. Hyaluronidases regulate WWOX expression, increase cancer invasiveness and seem to be involved in the development of hormone-independent growth of invasive cancer cells. Estrogen and androgen stimulate phosphorylation and nuclear translocation of WWOX, although binding of WWOX to these sex hormones is unknown. We propose that suppression of WWOX expression by overexpressed hyaluronidases might contribute in part to the development of hormone independence in invasive cancer.

Section snippets

WWOX is a candidate tumor suppressor

A candidate tumor suppressor WW domain-containing oxidoreductase (see Glossary), known as human WWOX [1] or FOR [2], or murine Wox1 or Wwox [3], was first discovered in 2000. The large size human gene WWOX (1.1 million base pairs) encodes this protein. Alterations of WWOX gene in cancer cells have been thoroughly investigated as documented in the literature, whereas functional properties of WWOX/Wwox are largely unknown. Here, we update the current knowledge of WWOX/Wwox regarding: (i)

WWOX: phosphorylation and degradation

WW domain was first discovered in 1996, and now the WW domain-containing proteins represent a large protein family (∼1400 members) 11, 12, 13. Functional deficiency of WW domain-containing proteins PIN1 [protein (peptidylprolyl cis/trans isomerase) NIMA-interacting 1] and WWOX might contribute to the pathogenesis of Alzheimer's disease 8, 14, 15. The solution structure of the second WW domain of human WWOX has been determined (//www.ncbi.nlm.nih.gov/Structure/mmdb/mmdbsrv.cgi%3Fform=6%26db=t%26Dopt=s%26uid=34568

WWOX: subcellular and tissue distribution

Subcellular localization of WWOX has been controversial. We have addressed this issue in two previous reviews 4, 21, and have tried to clarify it by using electron microscopy, as described below. Ectopic expression of murine Wwox, tagged with EGFP (green fluorescence protein) or ECFP (cyan fluorescence protein) in monkey kidney COS7 fibroblasts and lung H1299 cells, resulted in mitochondrial localization 3, 21. Endogenous Wwox is present in purified mitochondria from rat liver [3]. We have

WWOX: Tyr33 phosphorylation, death signaling and tumor suppression

WWOX/Wwox is a proapoptotic protein and tumor suppressor 3, 6, 19, 22, 25, 27, 28, 29, 30. Here, we summarize the known functional properties of human WWOX and mouse Wwox both in vivo and in vitro (Box 2).

Functional suppression of WWOX/Wwox by antisense mRNA, a dominant negative and small interfering RNA (siRNA), protects cells from apoptosis by tumor necrosis factor (TNF), staurosporine, ultraviolet (UV) light and ectopic p53 in vitro3, 25, 27. Ectopic WWOX suppresses growth of breast cancer

WWOX binding proteins

Both WW and SDR domains in WWOX/Wwox participate in protein-binding interactions. First, several PPxY motif-possessing proteins bind to the first WW domain, including p73 [19], activator protein-2γ (AP-2γ) [34], v-erb-a erythroblastic leukemia viral oncogene homolog 4 (ERBB4) [35], ezrin [23] and small integral membrane protein of the lysosome/late endosome (SIMPLE) [36] (Table 1 and Box 3). p73, AP-2γ and ERBB4 are transcription factors. Ezrin is a signal transducer located at the cell

Fragile gene WWOX–FRA16D

Human WWOX gene, which encodes WWOX, spans the common fragile site FRA16D on chromosome 16q23 1, 2, 32, 38, 39, 40, 41, 42, 43. Structurally, this gene is similar to fragile genes such as FHIT and PARKIN41, 42, 43. Many outstanding reviews have addressed the issues regarding loss of heterozygosity (LOH), deletions and translocations of WWOX gene in numerous types of cancers 32, 38, 39, 40, 41, 42, 43.

Briefly, high incidence of LOH is demonstrated in primary tumors, including carcinomas from

WWOX: prosurvival and role in differentiation?

Watanabe et al.[5] showed that WWOX protein levels are upregulated in non-invasive breast and gastric cancer tissues, raising the concern of whether WWOX is a typical tumor suppressor. By contrast, WWOX is markedly downregulated in these tissues during metastasis [5]. Significantly reduced expression of WWOX protein is also shown in invasive breast and prostate tissues 9, 29, 59. High-level expression of WWOX mRNA in estrogen receptor (ER)-positive breast cancer cells is associated with

WWOX: a prognostic marker for survival and role in hormone dependence

Cutaneous basal cell carcinoma (BCC) and SCC are the two most-common cancers in humans, and solar UV is the major environmental carcinogen responsible for the development of BCC and SCC [64]. In Drosophila model, WWOX blocks the lethal effects of ionizing radiation [60]. Upregulation of WWOX protein in the sunburn cells commits them to death, instead of developing into cancer [25]. Presumably, WWOX/Wwox-induced sunburn cell death serves as a cancer-preventive mechanism for eliminating

Hyaluronidases regulate WWOX gene expression: the good, the bad and the ugly

Hyaluronan and hyaluronidases are involved in embryonic development and are overexpressed in almost every type of cancer, and they are crucial for the progression of cancer towards malignancy and metastasis 67, 68, 69. Five family proteins of hyaluronidases have been identified [70]. Hyaluronidases HYAL1 and HYAL2 are products of the tumor suppressor gene lung cancer (LUCA). HYAL1, for example, might act as the promoter and suppressor of prostate-cancer growth [7]. Therapeutic hyaluronidase

Future directions

WWOX/Wwox has a crucial role in protection against cancer, and probably neurodegenerative diseases [8]. Alterations of WWOX/Wwox gene (e.g. LOH, methylation, etc.) are closely associated with cancer pathogenesis, progression and metastasis; however, a transgenic murine model for Wwox knockout is still lacking. If WWOX/Wwox has a tumor suppressor role, Wwox knockout mice are expected to develop tumors spontaneously. Drosophila mutants have provided an outstanding model for investigating the role

Concluding remarks

In summary, endogenous WWOX/Wwox seems to support embryonic development and differentiation, and probably has a homeostatic role in normal cell-cycle progression in concert with p53, p73, ERBB4 and other transcription factors. However, environmental stress can turn WWOX/Wwox into a proapoptotic protein. Cancer cells, however, are defective in producing WWOX at the invasive stage. Favorable clinical outcome in patients is associated with elevated expression of WWOX in cancer specimens. Thus, a

Acknowledgements

Research of N.S.C. was supported in part by the American Heart Association, the Department of Defense (DAMD17–03–1-0736), and the Guthrie Foundation for Education and Research. L.J.H. was supported by the Ministry of Education, Taiwan, ROC (91-B-FA09–1-4) and National Science Council, Taiwan (95–2320-B-006–072-MY2). We appreciate the critical review of this article by Dr. M. Sudol of the Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania, USA.

Glossary

Apoptosis
a form of cell death in which a programmed sequence of events leads to the elimination of cells without release of contents. Apoptosis can be triggered by many types of stress signals. When apoptosis does not occur in cells that should be eliminated, it might result in cancer. When apoptosis works overly well, it might cause neurodegenerative disorders such Alzheimer's and Parkinson diseases.
Common fragile site
a region that shows site-specific gap and break on metaphase chromosome.

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      The canonical transcript (ENST00000566780.5, NM_016373.3) encodes a 414–amino acid (aa) ubiquitous protein highly expressed in the prostate, gonads, breast, lung, endocrine tissues, and brain.21,22 Alternative splicing of WWOX during precursor messenger RNA (pre-mRNA) processing generates eight transcripts that have been observed only in cancers; whether every aberrant WWOX mRNA is translated into protein is unknown.23 The WW domain-containing oxidoreductase is the only protein that couples two distinct domains with high homologies with both the WW domain family and SRD superfamily.

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