circEZH2 E2 /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 has not been known whether EZH2 itself generates circRNAs that promote its own expression. We here report the identification of circEZH2 E2/E3 which is derived from exons 2 and 3 of EZH2 gene and overexpressed in PCa. We show that circEZH2 E2/E3 functions as a dual inhibitor for both miR363 and miR708 which targets EZH2 3'UTR and CDS, respectively, resulting in upregulation of EZH2 expression and hence 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 auto-enhancing 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.