Tumor suppressor WWOX binds to DNp63a 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 firstWW(WW1) domain. Here, we demonstrated that WWOX viaWW1 domain interacts with p53 homolog, DNp63a. This protein–protein interaction stabilizes DNp63a, through antagonizing function of the E3 ubiquitin ligase ITCH, inhibits nuclear translocation of DNp63a into the nucleus and suppresses DNp63a transactivation function. Additionally, we found that this functional crosstalk reverses cancer cells resistance to cisplatin, mediated by DNp63a, and consequently renders these cells more sensitive to undergo apoptosis. These findings suggest a functional crosstalk between WWOX and DNp63a in tumorigenesis.We are grateful to all members of the Aqeilan’s lab for their technical help and fruitful discussion. This work was supported, in part, by funds from Israel Science Foundation (ISF; #12-0542) to RIA and Israeli Cancer Research Funds (ICRF) to RIA and ZS