17 beta-Estradiol upregulates and activates WOX1/WWOXv1 and WOX2/WWOXv2 in vitro: potential role in cancerous progression of breast and prostate to a premetastatic state in vivo

Guthrie Research Institute, Laboratory of Molecular Immunology, 1 Guthrie Square, Sayre, PA 18840, USA.
Oncogene (Impact Factor: 8.56). 02/2005; 24(4):714-23. DOI: 10.1038/sj.onc.1208124
Source: PubMed

ABSTRACT Human WWOX gene encodes a proapoptotic WW domain-containing oxidoreductase WOX1 (also named WWOX, FOR2 or WWOXv1). Apoptotic and stress stimuli activate WOX1 via Tyr33 phosphorylation and nuclear translocation. WOX1 possesses a tetrad NSYK motif in the C-terminal short-chain alcohol dehydrogenase/reductase (SDR) domain, which may bind estrogen and androgen. Here, we determined that 17beta-estradiol (E(2)) activated WOX1, p53 and ERK in COS7 fibroblasts, primary lung epithelial cells, and androgen receptor (AR)-negative prostate DU145 cells, but not in estrogen receptor (ER)-positive breast MCF7 cells. Androgen also activated WOX1 in the AR-negative DU145 cells. These observations suggest that sex hormone-mediated Tyr33 phosphorylation and nuclear translocation of WOX1 is independent of ER and AR. Stress stimuli increase physical binding of p53 with WOX1 in vivo. We determined here that E(2) increased the formation of p53/WOX1 complex and their nuclear translocation in COS7 cells; however, nuclear translocation of this complex could not occur in MCF7 cells. By immunohistochemistry, we determined that progression of prostate from normal to hyperplasia, cancerous and metastatic stages positively correlate with upregulation and activation of WOX1 and WOX2 (FOR1/WWOXv2). In contrast, breast cancer development to a premetastatic state is associated with upregulation and Tyr33 phosphorylation of cytosolic WOX1 and WOX2, followed by significant downregulation or absent expression during metastasis. These Tyr33-phosphorylated proteins are mostly located in the mitochondria without translocating to the nuclei, which is comparable to those findings in cultured breast cancer cells. Together, sex steroid hormone-induced activation of WOX1 and WOX2 is independent of ER and AR, and this activation positively correlates with cancerous progression of prostate and breast to a premetastatic state.


Available from: Nan-Shan Chang, May 28, 2015
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    ABSTRACT: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT The human and mouse WWOX/Wwox gene encodes a candidate tumor suppressor WW domain-containing oxidoreductase protein. This gene is located on a common fragile site FRA16D. WWOX participates in a variety of cellular events and acts as a transducer in the many signal pathways, including TNF, chemotherapeutic drugs, UV irradiation, Wnt, TGF-β, C1q, Hyal-2, sex steroid hormones, and others. While transiently overexpressed WWOX restricts relocation of transcription factors to the nucleus for suppressing cancer survival, physiological relevance of this regard in vivo has not been confirmed. Unlike many tumor suppressor genes, mutation of WWOX is rare, raising a question whether WWOX is a driver for cancer initiation. WWOX/ Wwox was initially shown to play a crucial role in neural development and in the pathogenesis of Alzheimer's disease and neuronal injury. Later on, WWOX/Wwox was shown to participate in the development of epilepsy, mental retardation, and brain developmental defects in mice, rats and humans. Up to date, most of the research and review articles have focused on the involvement of WWOX in cancer. Here, we review the role of WWOX in neural injury and neurological diseases, and provide perspectives for the WWOX-regulated neurodegeneration. INTRODUCTION Human and mouse WWOX/Wwox gene was first cloned in year 2000 [1-5; reviews]. Later on, the mouse Wwox genome, which has one million bases, was isolated [6]. WW domain-containing oxidoreductase (designated WWOX, FOR, or WOX1) is a candidate tumor suppressor. This 46-KDa protein has two N-terminal WW domains and one C-terminal SDR (short-chain alcohol dehydrogenase/ reductase), plus a nuclear localization signal located in between the WW domains. Human WWOX gene, encoding the WWOX protein, has been mapped to a fragile site on the chromosome ch16q23.3-24.1 [1-5; reviews]. WW domains have been shown to interact with a wide variety of signaling proteins and functioning as adaptor proteins, transcriptional co-activators, and probably ubiquitin ligases. The first WW domain of WWOX binds a broad spectrum of PPxY-containing proteins, including p63, p73, AP-2γ (Activator protein 2γ), ErbB4 (v-Erb-B2 avian erythroblastic leukemia viral oncogene homolog 4), Runx-2 (Runt-related transcription factor 2), Dvl-2 (Dishevelled homolog protein-2), SIMPLE (Small integral membrane protein of the lysosome/late endosome), MET (MET proto-oncogene), LMP2A (viral latent membrane protein 2A), and others [1-13]. In stark contrast, when WWOX becomes Tyr33-phosphorylated in the first WW domain, it acquires an enhanced binding capability with PPxY motif-deficient proteins such as p53, JNK1 (c-Jun N-terminal kinase 1), c-Jun (Jun proto-oncogene), CREB (cAMP responsive element binding protein), and Zfra (Zinc finger-like protein that regulates apoptosis) [4,8,10-14]. Additionally, the C-terminal SDR domain of WWOX physically interacts with membrane hyaluronidase Hyal-2 [15], tau [16] and GSK-3β (Glycogen synthase
    Oncotarget 12/2014; 5(23):11792. · 6.63 Impact Factor
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    ABSTRACT: WW domain-containing oxidoreductase (WWOX) is a well-documented tumor suppressor protein that controls growth, survival, and metastasis of malignant cells. To counteract WWOX's suppressive effects, cancer cells have developed many strategies either to downregulate WWOX expression or to functionally inactivate WWOX. Relatively unknown is, in the context of those cancers associated with certain viruses or bacteria, how the oncogenic pathogens deal with WWOX. Here we review recent studies showing different strategies utilized by three cancer-associated pathogens. Helicobactor pylori reduces WWOX expression through promoter hypermethylation, an epigenetic mechanism also occurring in many other cancer cells. WWOX has a potential to block canonical NF-κB activation and tumorigenesis induced by Tax, an oncoprotein of human T-cell leukemia virus. Tax successfully overcomes the blockage by inhibiting WWOX expression through activation of the non-canonical NF-κB pathway. On the other hand, latent membrane protein 2A of Epstein-Barr virus physically interacts with WWOX and redirects its function to trigger a signaling pathway that upregulates matrix metalloproteinase 9 and cancer cell invasion. These reports may be just "the tip of the iceberg" regarding multiple interactions between WWOX and oncogenic microbes. Further studies in this direction should expand our understanding of infection-driven oncogenesis. © 2014 by the Society for Experimental Biology and Medicine.
    Experimental Biology and Medicine 12/2014; DOI:10.1177/1535370214561957 · 2.23 Impact Factor
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    ABSTRACT: Human fragile WWOX gene encodes a tumor suppressor WW domain-containing oxidoreductase (named WWOX, FOR, or WOX1). Functional suppression of WWOX prevents apoptotic cell death induced by a variety of stress stimuli, such as tumor necrosis factor, UV radiation, and chemotherapeutic drug treatment. Loss of WWOX gene expression due to gene deletions, loss of heterozygosity, chromosomal translocations, or epigenetic silencing is frequently observed in human malignant cancer cells. Acquisition of chemoresistance in squamous cell carcinoma, osteosarcoma, and breast cancer cells is associated with WWOX deficiency. WWOX protein physically interacts with many signaling molecules and exerts its regulatory effects on gene transcription and protein stability and subcellular localization to control cell survival, proliferation, differentiation, autophagy, and metabolism. In this review, we provide an overview of the recent advances in understanding the molecular mechanisms by which WWOX regulates cellular functions and stress responses. A potential scenario is that activation of WWOX by anticancer drugs is needed to overcome chemoresistance and trigger cancer cell death, suggesting that WWOX can be regarded as a prognostic marker and a candidate molecule for targeted cancer therapies. © 2015 by the Society for Experimental Biology and Medicine.
    Experimental Biology and Medicine 01/2015; DOI:10.1177/1535370214566747 · 2.23 Impact Factor