circEZH2E2/E3 is a dual suppressor of miR363/miR708 to promote EZH2 expression and prostate cancer progression

The histone methyltransferase enhancer of zeste homolog 2 (EZH2) is overexpressed in a variety of malignancies including prostate cancer (PCa) and may play important roles in tumor progression. Gene copy number gains, enhanced transcription, and a few circRNAs have been reported to upregulate EZH2. It was not known whether EZH2 itself generates circRNAs that promote its own expression. We here report the identification of circEZH2(E2/E3) that is derived from exons 2 and 3 of the EZH2 gene and overexpressed in PCa. We show that circEZH2(E2/E3) functions as a dual inhibitor for both miR363 and miR708 that target the EZH2 3 & PRIME;UTR and CDS, respectively, resulting in the upregulation of EZH2 expression and hence the downregulation of EZH2-repressed genes (e.g., CDH1 and DAB2IP), and enhancement of PCa cell proliferation, migration, invasion, and xenograft PCa growth. Overexpression of circEZH2(E2/E3) is significantly correlated with higher tumor grade, tumor progression, and unfavorable progression-free and disease-specific survival in PCa patients. These findings show a novel autoenhancing EZH2-circEZH2(E2/E3)-miR363/miR708-EZH2 regulatory loop, by which circEZH2(E2/E3) plays important roles in PCa tumorigenesis and progression by upregulating EZH2, and may have potential diagnostic, prognostic, and therapeutic uses in PCa management.