Hyaluronidases and hyaluronan are important mediators of tissue remodeling and cancer cell metastasis. Metastatic and malignant breast and prostate cancers frequently overexpress hyaluronidases and hyaluronan (1, 2). Hyaluronidases PH-20, Hyal-1, and Hyal-2 are known to induce the expression of a candidate tumor suppressor WW domaincontaining oxidoreductase WOX1 (also known as WWOX, FOR, or WWOXv1) (3-5).The human WWOX gene, which comprises nine exons encoding the WWOX/WOX1 family proteins, is located on a fragile site on the chromosome ch16q23.3-24.1 (6 -9). Eight mRNA transcripts of the WWOX gene have been found so far (7). However, it is still not known whether all of the mRNA transcripts are translated successfully into proteins. Isoforms WWOXv1 (46 kDa), WWOXv2 (42 kDa), and WWOXv8 (60 kDa) and several other small proteins can be found in normal and several types of cancer cells (3, 8 -11). 3 Genetic alterations of the WWOX gene and disappearance of WWOX/WOX1 family proteins have been shown in multiple types of cancers, especially at an invasive or a metastatic stage (8,9,(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Hypermethylation of the WWOX gene may inactivate its expression (21). In contrast, significant up-regulation of WWOX/WOX1 family proteins has been shown during progression of breast, prostate and other cancers to a premetastatic state (10,22,23). Also, absent expression of these family proteins in metastatic cancer cells is not necessarily due to disruption of the WWOX gene. We have recently determined that post-transcriptional blockade of the fulllength mRNA translation to protein may account for the disappearance of the WWOX/WOX1 family proteins in cutaneous squamous cell carcinoma cells in patients and in UVB-treated mice (24).Wild type WOX1 possesses two N-terminal WW domains (containing conserved tryptophan residues), a nuclear localization sequence and a C-terminal short-chain alcohol dehydrogenase/reductase domain (which contains a mitochondria-targeting sequence) (3). Sex steroid hormones such as estrogen and androgen activate WOX1 via Tyr 33 phosphorylation (p-WOX1) and nuclear translocation (11). Importantly, p-WOX1 is located in the mitochondria during benign prostatic hypertrophy (11). Nuclear translocation of p-WOX1 occurs when prostate cells progress toward cancerous and metastatic states (11), suggesting a critical role of WOX1 phosphorylation during prostate cancer development.We determined that WOX1 enhances the cytotoxic function of tumor necrosis factor (TNF) 4 and induces apoptosis when overexpressed (3). We also showed that in response to stress or apoptotic stimuli, WOX1 becomes phosphorylated at Tyr 33 , which allows its complex formation with activated p53 and JNK1 (25). The p53-WOX1 complex translocates to the mitochondria and nuclei to mediate apoptosis (25,26). WOX1 induces apoptosis synergistically with p53 (3,25). In contrast, JNK1 may block WOX1-induced cell death (25). Src is known to phosphorylate WOX1 at Tyr 33 (27). We also determined that Tyr 33 -phosphorylated WO...
