Loss of p63 and its microRNA-205 target results in enhanced cell migration and metastasis in prostate cancer

p63 inhibits metastasis. Here, we show that p63 (both TAp63 andΔNp63 isoforms) regulates expression of miR-205 in prostate cancer(PCa) cells, and miR-205 is essential for the inhibitory effects ofp63 on markers of epithelial–mesenchymal transition (EMT), suchas ZEB1 and vimentin. Correspondingly, the inhibitory effect ofp63 on EMT markers and cell migration is reverted by anti–miR-205. p53 mutants inhibit expression of both p63 and miR-205, andthe cell migration, in a cell line expressing endogenous mutatedp53, can be abrogated by pre–miR-205 or silencing of mutated p53.In accordance with this in vitro data, ΔNp63 or miR-205 significantlyinhibits the incidence of lung metastasis in vivo in a mousetail vein model. Similarly, one or both components of the p63/miR-205 axis were absent in metastases or colonized lymph nodes in aset of 218 human prostate cancer samples. This was confirmed inan independent clinical data set of 281 patients. Loss of this axiswas associated with higher Gleason scores, an increased likelihoodof metastatic and infiltration events, and worse prognosis. Thesedata suggest that p63/miR-205 may be a useful clinical predictor ofmetastatic behavior in prostate cancer.