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. 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 posttranscriptional mechanism regulating the plasticity of prostate cancer cells and provides a rationale for targeting miR-194 in this NEPC.

Mechanisms of enzalutamide resistance in castration‐resistant prostate cancer and therapeutic strategies to overcome it

“…Besides, microRNA‐194 (miR‐194) functions as a novel post‐transcriptional regulator of transdifferentiation in prostate cancer and is negatively correlated with signal‐axis androgen receptor. Notably, miR‐194 could trans‐differentiate prostate cancer cells into a neuroendocrine‐like cell by targeting FOXA1, which may contribute to enzalutamide resistance (Fernandes et al, 2019).…”

Mechanisms of Enzalutamide Resistance in Castration-Resistant Prostate Cancer and Therapeutic Strategies to Overcome It

“…functions as a novel post-transcriptional regulator of trans-differentiation in prostate cancer and is negatively correlated with signal-axis AR. Notably, miR-194 trans-differentiated PCa cells into a neuroendocrine-like cell by targeting FOXA1, which may contribute to Enz resistance (Fernandes, Toubia et al, 2019).…”