Polycomb Group protein EZH2-mediated transcriptional repression of microRNA-338/-421 drives SPINK1-positive prostate cancer

Serine Peptidase Inhibitor, Kazal type-1 (SPINK1) overexpression defines the second largest subtype of prostate cancer (PCa), however, molecular mechanisms underlying its upregulation remains poorly understood. Here, we identified a critical role of miRNA-338-5p and miRNA-421 in post-transcriptional regulation of SPINK1. We show that SPINK1-positive PCa patients also exhibit overexpression of Polycomb group member EZH2, which confers repressive trimethylation marks on lysine 27 of histone 3 (H3K27me3) on the regulatory regions of these miRNAs. Further, we demonstrate that oncogenic lncRNA MALAT1 interacts with EZH2, which in turn are targeted by miRNA-338-5p/miRNA-421, thus reinforcing a repressive molecular circuitry. Moreover, ectopic expression of miRNA-338-5p/-421 in SPINK1-positive PCa cells abrogate oncogenic properties including EMT, stemness and drug resistance, resulting in reduced tumor growth and distant metastases in mice. Collectively, we show that restoring miRNA-338-5p/miRNA-421 expression using epigenetic drugs or synthetic miRNA mimics could serve as a potential adjuvant therapy for treatment of SPINK1-positive malignancies.