MicroRNA-194 promotes lineage plasticity in advanced prostate cancer

ABSTRACT MicroRNA-194 (miR-194) promotes prostate cancer metastasis, but the precise molecular mechanisms by which it achieves this are unknown. Here, by integrating Argonaute high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (Ago-HITS-CLIP) with RNA sequencing and exon-intron split analysis, we defined a 163-gene miR-194 “targetome” in prostate cancer. These target genes were predominantly down-regulated through canonical 3’UTR recognition sites and were enriched within pathways involved in cytoskeletal organisation and cell movement. In clinical prostate cancer samples, miR-194 activity was inversely correlated with the androgen receptor (AR) signalling axis. At a mechanistic level, this inverse correlation was explained by down-regulation of miR-194 expression by AR. Accordingly, miR-194 expression and activity was significantly elevated in neuroendocrine prostate cancer (NEPC), an aggressive AR-independent disease subtype. MiR-194 enhanced the transdifferentiation of prostate adenocarcinoma cells to a neuroendocrine-like state, at least in part by targeting FOXA1, a transcription factor with a key role in maintaining the prostate epithelial lineage. Importantly, a miR-194 inhibitor effectively inhibited the growth of cell lines and patient-derived organoids with neuroendocrine features. Overall, our study reveals a novel post-transcriptional mechanism regulating the plasticity of prostate cancer cells and provides a rationale for targeting miR-194 in this NEPC.