Tumor suppressor WWOX binds to Delta DNp63 alpha and sensitizes cancer cells to chemotherapy

The WWOX tumor suppressor is a WW domain-containing protein. Its function in the cell has been shown to be mediated, in part, by interacting with its partners through its first WW(WW1) domain. Here, we demonstrated that WWOX via WW1 domain interacts with p53 homolog, Delta Np63 alpha. This protein-protein interaction stabilizes Delta Np63 alpha, through antagonizing function of the E3 ubiquitin ligase ITCH, inhibits nuclear translocation of DNp63a into the nucleus and suppresses Delta Np63 alpha transactivation function. Additionally, we found that this functional crosstalk reverses cancer cells resistance to cisplatin, mediated by Delta Np63 alpha, and consequently renders these cells more sensitive to undergo apoptosis. These findings suggest a functional crosstalk between WWOX and Delta Np63 alpha in tumorigenesis. Cell Death and Disease (2013) 4, e480; doi:10.1038/cddis.2013.6; published online 31 January 2013