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The development of novel therapies or the improvement of currently used approaches to treat prostate cancer (PCa), the most frequently diagnosed male tumor in developed countries, is an urgent need. In this regard, the functional characterization of microRNAs, molecules shown to regulate a number of cancer-related pathways, is instrumental to their possible clinical exploitation. Here, we demonstrate the tumor-suppressive role of the so far uncharacterized miR-1272, which we found to be significantly down-modulated in PCa clinical specimens compared to normal tissues. Through a gain-of-function approach using miRNA mimics, we showed that miR-1272 supplementation in two PCa cell models (DU145 and 22Rv1) reverted the mesenchymal phenotype by affecting migratory and invasive properties, and reduced cell growth in vitro and in vivo in SCID mice. Additionally, by targeting HIP1 encoding the endocytic protein HIP1, miR-1272 balanced EGFR membrane turnover, thus affecting the downstream AKT/ERK pathways, and, ultimately, increasing PCa cell response to ionizing radiation. Overall, our results show that miR-1272 reconstitution can affect several tumor traits, thus suggesting this approach as a potential novel therapeutic strategy to be pursued for PCa, with the multiple aim of reducing tumor growth, enhancing response to radiotherapy and limiting metastatic dissemination.