WW domain-containing oxidoreductase: a candidate tumor suppressor Nan-Shan Chang 1, 5 , Li-Jin Hsu 2, 3 , Yee-Shin Lin 2, 3 , Feng-Jie Lai 4 and Hamm-Ming Sheu 4 1 Institute of Molecular Medicine, National Cheng Kung University Medical College, Tainan, Taiwan 70101, Republic of China 2 Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan 70101, Republic of China 3 Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University Medical College, Tainan, Taiwan 70101, Republic of China 4 Department of Dermatology, National Cheng Kung University Medical College, Tainan, Taiwan 70101, Republic of China 5 Guthrie Research Institute, 1 Guthrie Square, Sayre, PA 18840, USA Common fragile site gene WWOX encodes a candidate tumor suppressor WW domain-containing oxidoreduc- tase. Alteration of this gene, along with dramatic down- regulation of WWOX protein, is shown in the majority of invasive cancer cells. Ectopic WWOX exhibits proapop- totic 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-indepen- dent growth of invasive cancer cells. Estrogen and androgen stimulate phosphorylation and nuclear trans- location 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. 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 Opinion TRENDS in Molecular Medicine Vol.13 No.1 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. Common fragile sites are normally stable in somatic cells. However, when cells are treated with replication inhibitors, fragile sites display gaps, breaks, rearrangements and other features of unstable DNA. The fragile sites and associated genes are frequently deleted or rearranged in many cancer cells that are considered a hallmark of genomic instability in cancer. Cutaneous basal cell carcinoma (BCC): a malignant neoplasm derived from pluripotential cells in the basal layer of epidermis or follicular structures. BCC is the most-common cancer in humans. The tumor characteristically develops on sun-exposed skin. BCC is usually slow growing and rarely metastasizes, but it can become invasive and cause substantial tissue damage if left untreated. Cutaneous squamous cell carcinoma (SCC): a malignant tumor derived from suprabasal keratinocytes of epidermis. SCC is the second most-common form of skin cancer. Predisposing factors for SCC include precursor lesions (actinic keratosis and Bowen’s disease), UV exposure, ionizing radiation and environ- mental carcinogens. SCC is capable of local invasion, regional lymph-node metastasis and distant metastasis. Fragile histidine triad (FHIT): a member of the histidine triad gene family that might act as a tumor suppressor. The gene encompasses the common fragile site FRA3B on human chromosome 3, where carcinogen-induced damage can lead to translocations and aberrant transcripts of this gene. Aberrant gene transcripts have been found in many cancers. Loss of heterozygosity (LOH): the loss of a single parent contribution to part of the genome in a cell. LOH of chromosomal regions bearing mutated tumor suppressor genes is a common event in the evolution of tumors. The remaining copy of the tumor suppressor gene will be often inactivated by a point mutation. LOH can arise by two ways. First, a region of a chromosome is deleted, resulting in only one copy remaining. Second, genetic recombination leaves the cell with two copies of the chromosomal region, but both come from the same parent. NSYK motif: a catalytic tetrad of NSYK (Asn–Ser–Tyr–Lys) present in most of SDR-containing protein family. SDR proteins mediate oxidation and reduction of lipid hormones and metabolic mediators. The NSYK motif in human WWOX is N232, S281, Y293 and K297. WWOX and its isoform WWOX2 are likely to bind to sex steroid hormones such as androgen and estrogen via the NSYK motif. p53: a tumor suppressor protein of 53 kDa. When DNA damage is minor, p53 halts the cell cycle until the damage is repaired. When DNA damage is major and cannot be repaired, p53 induces the cell to suicide by apoptosis. More than half of human cancers have p53 gene mutations and do not produce functioning p53 protein. Short-chain alcohol dehydrogenase–reductase (SDR): a large family of enzymes containing >2000 protein members, most of which are NAD- or NADP-dependent oxidoreductases. These proteins are of 250–300 amino acid residues, possessing at least two domains: the first domain binds to coenzyme(s) and the second to substrate(s). The second domain determines substrate specificity and contains amino acids that are involved in catalysis. Tumor necrosis factor: a member of a cytokine superfamily, which might induce tumor cell death and possess multiple proinflammatory functions. Tumor suppressor: protein product(s) of tumor suppressor gene(s) that slows down cell division or causes cell death to suppress tumor formation. Alterations of tumor suppressor gene(s) might induce cancer development. WW domain: a protein domain that is composed of a short stretch of 40 amino acids, possessing two conserved signature tryptophan residues. This domain folds as a stable, triple-stranded b-sheet, and can be repeated 2–4 times in proteins (Box 1). WW domain-containing proteins are normally involved in signal transduction by binding to proteins that possess proline motifs, PPxY (P, proline; Y, tyrosine; x, any amino acid), and/or phosphoserine- or phosphothreonine-containing motifs. WW domain-containing oxidoreductase (WWOX/Wwox): a candidate tumor suppressor and proapoptotic protein. The full-length protein, 46 kDa, pos- sesses two N-terminal WW domains, a nuclear localization sequence (NLS) and a C-terminal short-chain alcohol dehydrogenase–reductase (SDR) domain. Corresponding author: Chang, N.-S. (nschang13827@gmail.com). Available online 4 December 2006. www.sciencedirect.com 1471-4914/$ – see front matter ß 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.molmed.2006.11.006