Clinical behavior of prostate cancer (PCa) ranges from indolent disease to very aggressive tumors that rapidly progress to castration-resistance. However, the molecular mechanisms contributing to progression and clinical heterogeneity of PCa are still poorly understood. In this study we defined a novel oncogenic pathway involving miR-424 up-regulation and leading to altered stability of key oncogenic transcription factors, including STAT3. We found that miR-424 targets the E3 ubiquitin ligase COP1 and identified STAT3 as a key substrate of COP1 promoting tumorigenic and cancer stem-like properties in prostate epithelial cells. This oncogenic pathway is preferentially activated in a subgroup of prostate tumors characterized by reduced expression of the ETS factor ESE3/EHF and is associated with disease progression in prostate cancers. Monitoring the state of miR-424/COP1/STAT3 oncogenic axis could provide new insights for the development of specific therapeutic strategies and the identification of patients more likely to have aggressive tumor and disease recurrence.